diuretics 51/52 Flashcards
Acetazolamide (Diamox)
Carbonic Anhydrase Inhibitor
sulfonamide derivatives
inhib NaHCO3 reabsorption via CA @ the proximal tubule (organic acid secretory system) site of secretion and action
limited effectiveness: enhanced Na reabsorption (in the form of NaCl) by all the remaining tubule segments
not very effective diuretics; places further down in the tubule where Na+ (NaCl) can be reabsorbed
“amides”
Mannitol (Osmitrol)
Osmotic Diuretic
in EC space but doesn’t cross BBB
filtered by the glomeruli (no tubular secretion), with minimal tubular reabsorption
increase in the osmotic pressure of the glomerular filtrate, which leads to decreased reabsorption of water (and its solutes) in nephron segments that are freely permeable to water
Na+ follows the water- unique!
proximal tubule and descending limb of loop of Henle
Furosemide (Lasix)
Loop Diuretic/High ceiling Diuretic (Inhibitors of apical Na+‐K+‐2Cl‐ symport)
sulfonamide derivatives
Ethacrynic Acid (Edecrin)
Loop Diuretic/High ceiling Diuretic (Inhibitors of apical Na+‐K+‐2Cl‐ symport)
phenoxyacetic acid derivative
no sulfa like rxn!
but worse ototoxicity
Hydrochlorothiazide (Microzide)
Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport
Chlorothiazide (Diuril)
Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport
Chlorthalidone (Thalitone)
Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport
Indapamide
Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport
Triamterene (Dyrenium)
K+ sparing Diuretic (Inhibitor of renal Na+ Channels)
poorly soluble and may precipitate kidney stones
Amiloride
K+ sparing Diuretic (Inhibitor of renal Na+ Channels)
Spironolactone (Aldactone)
K+ sparing Diuretic (Aldosterone antagonist)
“-one”
Eplerenone (Inspra)
K+ sparing Diuretic (Aldosterone antagonists)
Drospirenone + ethinyl estradiol (Yasmin)
K+ sparing Diuretic (Aldosterone antagonists)
Desmopressin acetate (1‐Deamino‐8‐D‐Arginine Vasopressin) (DDAVP, Stimate)
Anti‐diuretic drug
similar in structure to arginine vasopressin (the antidiuretic hormone; ADH)
increases water reabsorption by the collecting duct system in the kidney, increase in the insertion of water channels in the apical membrane
greater antidiuretic activity than vasopressin itself but has less cardiovascular vasopressor activity
skip pgs
7,8,9, table pg 10
Most diuretics have in common the ability to ???
inhibit sodium reabsorption and thus promote sodium excretion–>promote water excretion
keep in mind the nephron segment where the diuretic acts and the capabilities of distal and proximal nephron segments
drugs acting proximal of the collecting duct increase the delivery of Na+ to the collecting duct and increase K+ excretion which causes hypokalemia
edema
in the interstitial space
generalized (ANASARCA = severe generalized edema)
OR
localized to a specific part of the body (e.g. hydrothorax, hydropericardium, ascites).
Edema is caused by
increased movement of fluid from the capillary intravascular space into the interstitial space
main factors influencing fluid movement in and out of the capillary
Capillary intravascular hydrostatic pressure (pushes out)
and plasma colloid osmotic pressure (pulls back in)- via plasma proteins
Factors that increase transudation (oozing like movement of fluid through a membrane or between cells) into the interstitium and cause edema:
Increase in capillary intravascular hydrostatic pressure
Decrease in capillary intravascular colloid osmotic pressure
Impaired lymphatic drainage of interstitial
Renal retention of salt and water
Increased capillary permeability
Increase in capillary intravascular hydrostatic pressure
*arteriolar dilation
venular constriction
increased venous pressure as in CHF
*venous obstruction
Decrease in capillary intravascular colloid osmotic pressure
- decreased production of plasma proteins
- increased loss of plasma proteins
accumulation of osmotically active substances in the interstitial
space
Impaired lymphatic drainage of interstitial (can’t tx with meds)
Obstruction, e.g. neoplastic blockage and Filariasis (elephantiasis)
Radical Mastectomy (destruction of lymphatics)
Renal retention of salt and water due to
(1) Kidney disease
(2) Liver disease
(3) Heart disease
Increased capillary permeability due to
inflammatory substances (histamines, kinins) i.e. anaphylactic shock
CHF ??
ventricular pumping is inadequate
CO is low
renal perfusion is decreased–>RAAS activated
both ventricles, so systemic (R) and pulmonary (L) edema
Edema associated with liver disease (Cirrhosis)
Decreased synthesis of plasma proteins (albumin) and thus lowered colloid osmotic pressure.
b. Decreased liver metabolism of sodium and water retaining hormones (e.g. aldosterone and vasopressin)
c. Scarring of liver tissue in cirrhosis increases hydrostatic pressure in the portal capillaries, the result is transudation of fluid into the peritoneum and the development of ascites.
d. decreased renal blood flow due to sequestration of fluid in the liver leads to compensatory renal retention of sodium and water.
Edema associated with renal disease
Nephrotic syndrome (aluminuria/hypoproteinemia–>dec. osmotic pressue–>edema)
Acute renal failure, prevent progression to irreversible failure
non-edematous uses of diuretics
HTN
Nephrolithiasis (kidney stones)
Hypercalcemia (Furosemide increases renal excretion of calcium)
Nephrogenic Diabetes Insipidus
Glaucoma therapy and Ocular surgery
Acute Mountain sickness
Urinary excretion of toxins, overdose treatment, prevention of renal toxicity
NOT for edema of pregnancy
Many kidney stones are caused by
too much renal leak of calcium. Thiazide diuretics enhance calcium reabsorption in the distal convoluted tubule and thus (by decreasing Ca++ excretion) are useful in patients with kidney stones (suggested that dietary NaCl be reduced)
Nephrogenic Diabetes Insipidus
paradoxical antidiuretic action of thiazide diuretics
dec. plasma volume, dec. glomerular filtration rate, inc. proximal reabsorption of NaCl and water, and dec. delivery of fluid to the diluting segments.
Mountain sickness is associated with
respiratory alkalosis, which leads to headache, irritability, anorexia, vomiting. Carbonic anhydrase inhibitors are useful due to induction of metabolic acidosis, and decreasing production of cerebral spinal fluid (CSF).
Acetazolamide (Diamox) SEs
SJS: sulfa hypersn. rxn
Hyperchloremic metabolic acidosis ‐ Bicarbonate wasting without much significant chloride excretion
Urinary alkalinization can lead to precipitation of calcium phosphate, which may lead to kidney stones.
Some hypokalemia because of K+ excretion
Contraindicated in hepatic cirrhosis
Acetazolamide (Diamox) uses: Glaucoma
Glaucoma ‐ Inhibition of CA decreases intraocular pressure by decreasing aqueous humor formation
topical
Acetazolamide uses: mountain sickness
provide relief from the respiratory alkalosis and cerebral edema
due to induction of metabolic (non-respiratory) acidosis and decreased production of CSF
Acetazolamide uses: epilepsy
again due to the induction of metabolic acidosis and CNS actions
Acetazolamide uses: Urinary alkalinization
can enhance renal excretion of weak acids (uric acid, aspirin)
Acetazolamide uses: correct metabolic alkalosis
cause metabolic acidosis
*if too great may cause kidney stones
mannitol uses
oliguric acute renal failure
reduction of intraocular and intracranial pressure (increasing plasma osmotic pressure)
Urinary excretion of toxins/overdose treatment/prevention of renal toxicity
mono or combo for peripheral edemas of nephrotic, cirrhotic and cardiac origins
mannitol SEs
extract too much water from peripheral intracellular stores and this increases the extracellular fluid volume: CHF pt: more pulmonary edema
hyponatriemia
CI in severe renal disease, cranial bleeding
hyperglycemia (Glycerin metabolism)
loop diuretics:
Furosemide (Lasix)
Ethacrynic Acid (Edecrin)
secreted by the proximal tubule via organic acid secretion mechanism
-uric acid will buildup from competition, bad for gout pts**
act in thick ascending limb of Henle’s loop where they block the Na+‐K+‐2Cl‐ symporter in the luminal (apical) membrane (incr. excretion of these 3 ions)
high‐ceiling diuretics because of the high reabsorptive capacity of the thick ascending limb (25%)
The diuresis results in enhanced excretion of not only Na+ and Cl‐, but also K+, H+, Ca++, Mg++, ammonium and possibly phosphate
loop diuretic uses
CHF acute pulmonary edema HTN (thiazides better, longer half lives) hypercalcemia (inc. excretion) Edema of nephrotic syndrome Edema with liver cirrhosis OD hyponatremia
loop diuretics SEs
PROFOUND e-lyte and fluid loss: hypotension, hypovolemia, hyponatremia
inc. K+/H+ excretion: hypochloremic metabolic alkalosis and hypokalemia
metabolic: hyperglycemia and increased plasma levels of LDL and triglyceride
gout exacerbation
ototoxicity (more common w/ ethacrynic acid, also with amino glycoside abx tx (i.e. Gentamicin)
sulfa-like rxns
Hypomagnesemia
lithium toxicity
dec. effects by NSAIDS
thiazides get into kidney via
filtered by the glomerulus and also sec. by organic acid secretory mech in proximal tubule
–>competition for uric acid–>gouty
-bound heavily to plasma proteins
where/how thiazides inhibit Na reabsorb
inhibit the Na+‐Cl‐ symporter in the *luminal (apical) membrane of the early distal convoluted tubule (cortical diluting segment) promoting NaCl excretion and water diuresis.
Diuretic action is independent of patient acid‐base balance
thiazide uses
mild-moderate edema of heart failure (loop diuretice for more severe, esp. if GFR drops below 30 ‐ 40 ml/min)
HTN
kidney stones (nephrolithiasis), osteoporosis
Nephrogenic diabetes insipidus
ascites due to liver cirrhosis
Nephrogenic diabetes insipidus
Paradoxical antidiuretic effect ‐ reduce urine volume up to 50% due to plasma volume contraction leading to fall in GFR with associated increased proximal tubular
reabsorption.
kidney stones (nephrolithiasis), osteoporosis thiazide mechanism
indirectly inc. reabsorption (dec. excretion) of Ca2+ from urine in distal convoluted tubule
-dependent on steeper Na+ gradient (Na+ reab. inhibitited, so pumped into cell, Ca2+ pumped out into blood)
thiazide SEs
Hypokalemia and metabolic alkalosis due to excretion of K+ and H+ in the late distal tubule and cortical collecting duct
Gout ‐ decreased excretion of uric acid
sulfonamide hypersensitivity
hyperglycemia
inc. plasma LDL cholesterol, total cholesterol, and total triglycerides (not: Indapamide)
hyperglycemia (dec. insulin secretion)
How do K+ wasting diuretics waste K+?
Goodman+Gilman theory
diuretics which increase delivery of Na+ to the collecting duct system are K+ wasting because they: inc. Na+ conductance (movement) through a luminal (apical) channel leading to a lumen negative transepithelial voltage which indirectly promotes inc. K+ secretion
-also pulls H+, causes alkalosis in blood
theory failure: not nec. inc. in NET Na+
How do K+ wasting diuretics waste K+?
Peuler’s theory
increase delivery of both Na+ AND Cl‐ to the collecting duct system where Na+ uptake via the cellular luminal (apical) Na+ channels occurs at a disportionately faster rate than Cl‐ uptake via the paracellular route. Obviously, this leaves the urine remaining here in the lumen more negatively charged thus attracting more secretion (and therefore excretion) of positively‐charged K+ (and H+) at this site.
loop and thiazide diuretics:
one more thing that contributes to K+ wasting
Compensatory increase in activity of the renin‐angiotensin‐aldosterone system (RAAS), if it occurs, can also contribute to K+ wasting here due to the known actions of aldosterone:
facilitates Na+/K+ ATPase
K+ sparing diuretics:
Triamterene (Dyrenium)
Amiloride
get into kidney via organic BASE secretory mech in the proximal tubule (don’t worry about uric acid buildup)
Both amiloride and thriamterene act on the *principal cells in the collecting duct system where they inhibit luminal (apical) Na+ channels , which obviously inhibits Na+ reabsorption
secretion by making the urine in the lumen
but also indirectly inhibits K+ secretion by making the urine in the lumen more positively charged
less H+ secretion by the intercalated cells of the collecting duct system.
K+ sparing diuretics: Triamterene
Amiloride uses
not powerful diuretics since collecting duct system reabsorbs only 3% of the filtered load of Na+ and Cl‐ (this may or may not be true for aldosterone receptor antagonists)
Thus, because of limited diuretic capacity, these agents are mostly used in combination with other diuretics (thiazide, loop diuretic) to treat edema (CHF, hepatic cirrhosis, hyperaldosteronism), and hypertension
used to counterbalance the hypokalemia caused by thiazide and loop diuretics.
other K+ sparing diuretics (Triamterene,
Amiloride) uses
CF
Liddle’s syndrome
Liddle’s syndrome
defect in the collecting duct system such that these cells respond as if they are exposed to high levels of aldosterone ( Na+ reabsorption, K+ secretion, H+ secretion) ‐ The result is hypokalemic metabolic alkalosis and hypertension. (pseudohyperaldosteronism)
Amiloride and Triamterene are useful in offsetting this condition by blocking sodium channels.
amiloride and triamterene SEs
life‐threatening hyperkalemia: (cardiac arrhythmias, muscle weakness) and thus also contraindicated in hyperkalemic patients and with the use of K+ supplements.
N/V kidney stones (triamterene)
amiloride and triamterene should not be administered with ?? due to risk of life‐ threatening hyperkalemia
aldosterone receptor blockers (e.g. spironolactone)
K+‐sparing diuretics should be used with caution with blockers of the
?? due to risk of
hyperkalemia.
renin‐angiotensin‐aldosterone system (RAAS)
K+ sparing Diuretics (Aldosterone receptor blockers) ‐
Spironolacatone (Aldactone) and Eplerenone (Inspra), Drospirenone
antagonists (blockers) at mineralocorticoid receptors (aldosterone receptors). Binding to the receptor prevents aldosterone‐induced gene transcription
clinical efficacy of these drugs is dependent on the levels of endogenous aldosterone
K+ sparing Diuretics (Aldosterone receptor blockers) block aldosterone effects:
main effects of the hormone aldosterone in the collecting duct system are Na+ conductance out of the lumen to inside of cells via more Na channel activity and basolateral Na+/K+‐ATPase activity, and thus indirectly secretion of K+ and H+ (due to increased lumen electronegativity as well as the increased basolateral Na+/K+ exchange). Accordingly, aldosterone receptor blockers block these effects.
spironolactone and eplerenone usually administered with a loop diuretic or thiazide diuretic to treat edema and hypertension. Helps by ??
also effective in treating ??
reducing edema fluid and preventing hypokalemia.
hyperaldosteronism (primary or secondary)
spironolactone and eplerenone diuretics of choice for
CHF, hepatic cirrhosis (edema)
Toxicity, adverse reactions, and contraindications: spironolactone and eplerenone
If used alone (except perhaps in high aldo states) can induce life‐ threatening hyperkalemia (cardiac arrhythmias, muscle weakness) and thus also contraindicated in hyperkalemic patients and with the use of K+ supplements
Use with another K+ sparing diuretic (amiloride, triamterene) is obviously also contraindicated.
Antiandrogen effects (Spironoloactone more so than >Eplerenone (more selective))
Use with caution with drugs that block RAAS (e.g. ACE inhibitors) due to increased risk of hyperkalemia
?? is considered a more selective antagonist at just mineralcorticoid (aldosterone) receptors, and unlike spironolactone it appears not to interact with androgen receptors, glucocorticoid receptors and progesterone receptors.
Eplerenone
desmopressin uses
Nocturnal enuresis, due to neurogenic, Central (pituitary) Diabetes
insipidus (i.e. lack of vasopressin secretion; DDAVP is drug of choice).
desmopressin SEs
Water intoxication, use with caution in patients with angina, hypertension and heart failure
diuretic SE case study (pg. 26, important!***)
muscle cramps, painful toe, prescribed hydrochlorothiazide
-high uric acid
-low K+
why musc. cramps and constipation?
hypokalemia: destabilize muscle cell membranes
-dangerous, can lead to heart failure
can also have problem with hyperkalemia
warning sign to cardiac failure due to hypokalemia
(could also have this situation with HYPERkalemia)
why hypokalemia from thiazide
secondary explanation for hypokalemia (thiazide-induced)
correct by ??
increasing Na+ delivery to collecting duct system, increasing Na+/K+ exchange later in tubule, increasing K+ wasting in urine
reduction in BV can BP can activate compensatory RAAS and inc. aldosterone inc. K+ secretion
correct by eat bananas, potatoes, etc.
K+ supplements
or K+ sparing diuretics
gout brought on by
thiazides inc. uric acid: inhibit uric acid secretion in proximal tubule (organic acid secretory mechanism)
diuretic-induced hypovolemia
summary:
Carbonic Anhydrase Inhibitor: Acetazolamide
works where ??
does what ??
Proximal Tubule
and distal tubule
Inhibit carbonic anhydrase
decrease Na+‐H+ exchange
increase NaHCO3 diuresis
summary:
Osmotic Diuretic: Mannitol
works where ??
does what ??
Proximal Tubule and Loop of Henle
increase osmotic Pressure
decrease reabsorption of water and solutes
summary:
Loop Diuretics: Furosemide, Ethacrynic Acid
work where ??
do what ??
Loop of Henle (thick ascending limb)
Inhibit Na+‐K+‐2Cl‐ symporter
summary:
Thiazide and Thiazide‐like diuretics: Hydrochlorothiazide Chlorthalidone
work where ??
do what ??
Distal Convoluted Tubule
Inhibit Na+‐Cl‐ symporter
summary:
K+ sparing Diuretics: Triamterene and Amiloride
work where ??
do what ??
Late distal tubule and collecting Duct
Block Na+ channels
decrease secretion of K+ and H+
summary:
K+ sparing Diuretics: Spironolactone and Eplerenone
work where ??
do what ??
Late distal tubule and collecting Duct
Aldosterone Antagonist
decrease Na+ conductance
decrease Na+/K+‐ATPase activity decrease secretion of K+ and H+
