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Flashcards in diuretics 51/52 Deck (77):
1

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"

2

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*

3

Furosemide (Lasix)

Loop Diuretic/High ceiling Diuretic (Inhibitors of apical Na+‐K+‐2Cl‐ symport)

sulfonamide derivatives

4

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

5

Hydrochlorothiazide (Microzide)

Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport

6

Chlorothiazide (Diuril)

Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport

7

Chlorthalidone (Thalitone)

Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport

8

Indapamide

Thiazide and thiazide‐like diuretic (Inhibitor of apical Na+‐Cl‐symport

9

Triamterene (Dyrenium)

K+ sparing Diuretic (Inhibitor of renal Na+ Channels)

poorly soluble and may precipitate kidney stones

10

Amiloride

K+ sparing Diuretic (Inhibitor of renal Na+ Channels)

11

Spironolactone (Aldactone)

K+ sparing Diuretic (Aldosterone antagonist)
("-one")

12

Eplerenone (Inspra)

K+ sparing Diuretic (Aldosterone antagonists)

13

Drospirenone + ethinyl estradiol (Yasmin)

K+ sparing Diuretic (Aldosterone antagonists)

14

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


15

skip pgs

7,8,9, table pg 10

16

Most diuretics have in common the ability to ???

inhibit sodium reabsorption and thus promote sodium excretion-->promote water excretion

17

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

18

edema

in the interstitial space

generalized (ANASARCA = severe generalized edema)
OR
localized to a specific part of the body (e.g. hydrothorax, hydropericardium, ascites).

19

Edema is caused by

increased movement of fluid from the capillary intravascular space into the interstitial space

20

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

21

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

22

Increase in capillary intravascular hydrostatic pressure

*arteriolar dilation

venular constriction

increased venous pressure as in CHF

*venous obstruction

23

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

24

Impaired lymphatic drainage of interstitial (can't tx with meds)

Obstruction, e.g. neoplastic blockage and Filariasis (elephantiasis)

Radical Mastectomy (destruction of lymphatics)

25

Renal retention of salt and water due to

(1) Kidney disease
(2) Liver disease
(3) Heart disease

26

Increased capillary permeability due to

inflammatory substances (histamines, kinins)
i.e. anaphylactic shock

27

CHF ??

ventricular pumping is inadequate
CO is low
renal perfusion is decreased-->RAAS activated

both ventricles, so systemic (R) and pulmonary (L) edema

28

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.

29

Edema associated with renal disease

Nephrotic syndrome (aluminuria/hypoproteinemia-->dec. osmotic pressue-->edema)

Acute renal failure, prevent progression to irreversible failure

30

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

31

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)

32

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.

33

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).

34

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

35

Acetazolamide (Diamox) uses: Glaucoma

Glaucoma ‐ Inhibition of CA decreases intraocular pressure by decreasing aqueous humor formation

topical

36

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

37

Acetazolamide uses: epilepsy

again due to the induction of metabolic acidosis and CNS actions

38

Acetazolamide uses: Urinary alkalinization

can enhance renal excretion of weak acids (uric acid, aspirin)

39

Acetazolamide uses: correct metabolic alkalosis

cause metabolic acidosis

*if too great may cause kidney stones

40

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

41

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)

42

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

43

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

44

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


45

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

46

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

47

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

48

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.

49

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)

50

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)

51

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+

52

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.

53

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

54

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.

55

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.

56

other K+ sparing diuretics (Triamterene,
Amiloride) uses

CF
Liddle's syndrome

57

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.

58

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)

59

amiloride and triamterene should not be administered with ?? due to risk of life‐ threatening hyperkalemia

aldosterone receptor blockers (e.g. spironolactone)

60

K+‐sparing diuretics should be used with caution with blockers of the
?? due to risk of
hyperkalemia.

renin‐angiotensin‐aldosterone system (RAAS)

61

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

62

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.

63

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)

64

spironolactone and eplerenone diuretics of choice for

CHF, hepatic cirrhosis (edema)

65

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

66

?? 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

67

desmopressin uses

Nocturnal enuresis, due to neurogenic, Central (pituitary) Diabetes
insipidus (i.e. lack of vasopressin secretion; DDAVP is drug of choice).

68

desmopressin SEs

Water intoxication, use with caution in patients with angina, hypertension and heart failure

69

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)

70

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

71

gout brought on by

thiazides inc. uric acid: inhibit uric acid secretion in proximal tubule (organic acid secretory mechanism)

diuretic-induced hypovolemia

72

summary:
Carbonic Anhydrase Inhibitor: Acetazolamide
works where ??
does what ??

Proximal Tubule
and distal tubule

Inhibit carbonic anhydrase 
decrease Na+‐H+ exchange
increase NaHCO3 diuresis

73

summary:
Osmotic Diuretic: Mannitol
works where ??
does what ??

Proximal Tubule and Loop of Henle

increase osmotic Pressure
decrease reabsorption of water and solutes

74

summary:
Loop Diuretics: Furosemide, Ethacrynic Acid
work where ??
do what ??

Loop of Henle (thick ascending limb)

Inhibit Na+‐K+‐2Cl‐ symporter

75

summary:
Thiazide and Thiazide‐like diuretics: Hydrochlorothiazide Chlorthalidone
work where ??
do what ??

Distal Convoluted Tubule

Inhibit Na+‐Cl‐ symporter

76

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+

77

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+