L36 Diuretics Flashcards
(146 cards)
1
Q
How do the kidneys control the ECF volume?
A
By adjusting NaCl and H2O excretion
2
Q
The glomeruli produce ___ ml/min ultrafiltrate; ___ ml/min of urine is formed.
A
120; 1
3
Q
To maintain NaCl balance, approximately ___ lbs of NaCl must be reabsorbed by the renal tubules on a daily basis.
A
3
4
Q
What happens when NaCl intake exceeds output?
A
Edema develops
5
Q
What do diuretics do, generally?
A
Increase urine volume, Na+ excretion, and Cl- excretion; they reduce ECF volume by decreasing NaCl content
6
Q
What is reabsorption?
A
Movement of a substance from the tubule to the blood
7
Q
What is secretion?
A
Movement of a substance from the blood to the tubule
8
Q
What is excretion?
A
Movement of a substance from the collecting tubule into the urine
9
Q
What is reabsorbed in the proximal convoluted tubule?
A
85% of filtered HCO3 60% of filtered NaCl 60% of water 80-90% of filtered K+ 70% of filtered Ca2+ 100% of organic solutes
10
Q
What is reabsorbed in the thin descending limb of the Loop of Henle?
A
Water
11
Q
What is reabsorbed in the thick ascending limb of the Loop of Henle?
A
25% NaCl
NO water
25% Ca2+
100% Mg2+
12
Q
What is reabsorbed in the distal convoluted tubule?
A
10% NaCl
NO water
5% Ca2+ (regulated by PTH)
13
Q
What is reabsorbed in the collecting tubule?
A
2-5% NaCl
Water (regulated by ADH)
14
Q
What is secreted in the collecting tubule?
A
K+ and H+ (regulated by aldosterone)
15
Q
Where does acetazolamide act and what does it do, broadly?
A
Inhibits CA in the proximal convoluted tubule, leading to inhibition of 85% of NaHCO3 reabsorption
16
Q
Where do osmotic agents (mannitol) act and what do they do, broadly?
A
Limits water reabsorption in the water-permeable segments of the nephron - PCT, TDL, CT (when ADH is present)
17
Q
Where do loop diuretics (Lasix) act and what do they do, broadly?
A
Inhibits Na/K/2Cl cotransport in the thick ascending limb of Henle’s loop
18
Q
Where do thiazides act and what do they do, broadly?
A
Inhibit NaCl co-transport in the distal convoluted tubule
19
Q
Where do potassium sparing diuretics act and what do they do, broadly?
A
Inhibit aldosterone actions or Na+ channels in the collecting tubule
20
Q
Where do ADH antagonists act and what do they do, broadly?
A
Prevent ADH-stimulated reabsorption of water in the collecting tubule
21
Q
What is the primary therapeutic goal of diuretic use?
A
Reduction of edema
22
Q
Except for spironolactone and some ADH antagonists, diuretics generally exert their effects…
A
…from the luminal side of the nephron
23
Q
How do most diuretics (besides mannitol) get into the tubule fluid?
A
Secretion across the PT (organic acid/base secretory pathway)
24
Q
How does mannitol get into the tubule fluid?
A
Filtration at the glomerulus
25
What two major issues can reduce diuretic effectiveness?
1. Decreased renal blood flow/renal failure
| 2. Drugs that compete for the secretory pump
26
Which drug competes for acidic drugs? Which drug competes for basic drugs?
Acidic: probenecid
Basic: cimetidine
27
The apical side of the epithelial cells face the ___; the basolateral side faces the ___.
Lumen; blood
28
What drives sodium reabsorption in tubule epithelial cells?
Na/K ATPase at the basolateral side of the epithelial cells (3 Na out, 2K in)
29
Describe the Na and K concentrations in the tubule epithelial cells.
Low Na, High K
30
Describe the ion transport in the proximal convoluted tubule.
Apical side:
1. Na/H exchanger (Na in, H out)
2. Cl/base exchanger (Cl in, base out)
Inside the cell: CA converts CO2 and H2O to H2CO3, which becomes H+ and HCO3. The H+ is used in the Na/H exchanger. the HCO3 is used on the basolateral side.
Basolateral side:
1. Na/K ATPase (K in, Na out)
2. HCO3 transporter (out)
31
What is the net effect of transport in the PCT?
Reabsorption of Na+ and bicarbonate
32
What is the MOA of acetazolamide?
Reversible inhibition of CA
33
What are the pharmacodynamics of acetazolamide?
Inhibition of reabsorption of bicarbonate in the PCT
34
Describe the absorption and timing of effects of acetazolamide.
Well-absorbed orally
Effect begins in 30 minutes, maximum at 2 hours
Duration of effect: 12 hours
35
How does acetazolamide get into the tubule?
Organic acid transporter
36
What are the adverse effects of acetazolamide?
1. Metabolic acidosis
2. Hypokalemia
3. Calcium phosphate stones
4. Drowsiness, parasthesias
5. Hypersensitivity
37
What are the contraindications of acetazolamide?
1. Cirrhosis (increased urine pH reduces NH3 secretion, increasing serum NH3)
38
What are the 3 other CA inhibitors?
1. Dichlorphenamide
2. Methazolamide
3. Dorzolamide
39
Discuss the relative potencies of dichlorphenamide and methazolamide to acetazolmide.
Dichlorphenamide: 30x more potent
Methazolamide: 5x more potent
40
How is dorzolamide used?
Topically for ocular use
41
What are the clinical indications of acetazolamide?
1. Diuretic agent (weak, okay backup)
2. Glaucoma
3. Urinary alkalinization (OD, stones)
4. Acute mountain sickness
42
What is the MOA of mannitol?
Osmotic diuresis in PCT, DTL, CT (w/ADH)
43
Discuss the pharmacodynamics of mannitol.
Expansion of intravascular volume that leads to a powerful diuretic effect once it reaches the kidney
44
Describe the absorption and half-life of mannitol.
IV injection only; half-life = 1.2 hours
45
Generally, when are adverse effects seen with mannitol?
When filtration is impaired
46
What are the adverse effects of mannitol?
1. Reduced GFR retains mannitol in the ECF, which moves water out of the cells into the ECF, worsening edema/heart failure. Na+ follows, leading to hyponatremia.
2. Acute pulmonary edema
3. Dehydration
4. Headache/nausea/vomiting
47
What are the contraindications of mannitol?
CHF, renal failure, pulmonary edema
48
What are the clinical indications of mannitol?
1. Maintain/increase urine volume (treat/prevent acute renal failure, promote excretion of toxic substances)
2. Reduce intracranial pressure
3. Glaucoma
49
What is the difference in epithelium in the thin and thick segments of the Loop of Henle?
Thin: simple squamous
Thick: simple cuboidal
50
Describe the ion transport in the thick ascending limb.
Apical:
1. Na/K/2Cl cotransporter (all 3 in)
2. K transporter (out) - creates + charge in lumen, which drives paracellular diffusion of Ca2+/Mg2+ into the blood
Basolateral:
1. Na/K ATPase (K in, Na out)
2. K/Cl transporter (both out)
51
What is the most efficacious diuretic class?
Loop diuretics
52
What is the MOA of furosemide (Lasix)?
Inhibition of Na/K/Cl cotransport & vasodilation
53
What are the pharmacodynamics of furosemide?
Inhibition of the cotransporter reduces Na/K/Cl reabsorption, as well as Ca2+/Mg2+ due to loss of + luminal charge
Renal vasodilation improves renal blood flow
54
Describe the absorption, half-life, and duration of furosemide.
Rapid oral absorption; 1-1.5 hours half-life; duration = 2-3 hours
55
How does furosemide get into the tubules?
Organic acid transporter
56
What are the adverse effects of furosemide?
1. Hyponatremia/hypokalemia/hypomagnesemia
2. Dehydration
3. Metabolic alkalosis
4. Mild hyperglycemia
5. Ototoxicity
6. Hypersensitivity
57
What are the indications of furosemide?
1. Acute pulmonary edema
2. Edema w/CHF
3. Acute hypercalcemia
4. Acute hyperkalemia
5. Hypertension
58
What are the 3 other loop diuretics?
1. Bumetanide
2. Torsemide
3. Ethacrynic acid
59
Discuss the relative potency of bumetanide compared to furosemide.
40x more potent
60
Discuss the relative half-lives of bumetanide and torsemide compared to furosemide.
Bumetanide: 1 hour
Torsemide: 3 hours (5-6 hour duration of action)
61
Which loop diuretic has better oral absorption that furosemide?
Torsemide
62
Why is ethacrynic acid a last resort?
Used only when others exhibit hypersensitivity, as it is nephrotoxic and ototoxic
63
Describe the ion transport in the distal convoluted tubule.
Apical:
1. Na/Cl transporter (both in)
2. Ca2+ channel (in)
Basolateral:
1. Na/K ATPase (K in, Na out)
2. Na/Ca antiporter (Na in, Ca out)
3. Receptor for PTH
64
What does PTH control in the DCT?
Ca2+ reabsorption
65
What is the most commonly used class of diuretics?
Thiazides
66
What is the MOA of hydrochlorothiazide?
Inhibition of Na/Cl contransporter in the distal tubule
67
What are the pharmacodynamics of hydrochlorothiazide?
Produces relatively mild diuresis and increased Ca2+ reabsorption
68
Describe the absorption and half-life of hydrochlorothiazide.
Good oral; half-life = 2.5 hours
69
What are the adverse effects of hydrochlorothiazide?
1. Hyponatremia/hypokalemia
2. Dehydration
3. Metabolic alkalosis
4. Hyperuricemia
5. Hyperglycemia
6. Hyperlipidemia (increased LDL)
7. Weakness, fatigue, paresthesias
8. Hypersensitivity
70
What are the indications of hydrochlorothiazide?
1. Hypertension
2. CHF
3. Reduced Ca2+ excretion to prevent kidney stones
71
What are 4 other thiazide diuretics?
1. Chlorothiazide
2. Metolazone
3. Indapamide
4. Chlorthalidone
72
Discuss the relative potencies and half-lives of the 4 thiazide diuretics to hydrochlorothiazide.
Chlorothiazide: 1/10 potency, 1.5 hours half life
Metolazone: 10x more potent, 4-5 hours half life
Indapamide: 20x more potent, 10-22 hours half life
Chlorthalidone: same potency, 44 hour half-life
73
What is the most efficacious thiazide diuretic?
Metolazone
74
What are the two types of cells in the collecting tubules?
Principal and intercalated
75
Describe the ion transport in the principal cells of the collecting tubule.
Apical:
1. Na, K, H2O channels (Na/H2O in, K out)
2. Cl- (paracellular transport in - net negative charge of Na absorption > K secretion repels Cl- and attracts K into the lumen)
Basolateral:
1. Na/K ATPase (K in, Na out)
76
___ regulates expression of Na/K ATPase and channels in the principal cells.
Aldosterone
77
___ regulates water channels and water reabsorption in the principal cells.
ADH
78
Describe the ion transport in the intercalated cells of the collecting tubule.
Apical:
1. H+ ATPase (H+ out)
Basolateral:
1. HCO3/Cl antiporter (HCO3 out, Cl in)
79
The H+ ATPase of the intercalated cells is regulated by ___.
Aldosterone
80
Discuss how hypokalemia arises in the setting of acetazolamide and other CA inhibitors.
These drugs increase HCO3 in the tubule, leading to increased lumen negative potential. In the collecting tubule, this enhances K+ efflux from the principal cells, leading to hypokalemia.
81
Discuss how hypokalemia arises in the setting of loop and thiazide diuretics.
These drugs increase Na/Cl, leading to increased lumen negative potential. In the collecting tubule, this enhances K+ efflux from the principal cells, leading to hypokalemia.
82
Discuss how metabolic alkalosis arises in the setting of loop and thiazide diuretics.
These drugs increase Na/Cl, leading to increased lumen negative potential. In the collecting tubule, this enhances H+ efflux from the intercalated cells, leading to metabolic alkalosis.
83
What are potassium sparing diuretics?
Agents often given to avoid hypokalemia that accompanies CA inhibitors, loop diuretics, and thiazide diuretics
84
When are potassium sparing diuretics contraindicated?
Setting of hyperkalemia or in patients on drugs or with diseases states likely to cause hyperkalemia (diabetes mellitus, multiple myeloma, tubulointerstitial renal disease, renal insufficiency)
85
What are 2 common drugs that can cause hyperkalemia?
Potassium supplements and ACE inhibitors
86
What is the MOA of spironolactone?
Competitive inhibition of the aldosterone receptor + anti-androgenic effects (decreases testosterone synthesis, competitively inhibits DHT receptor)
87
Discuss the pharmacodynamics of spironolocatone.
Causes mild diuresis due to decreased Na+ reabsorption secondary to aldosterone inhibition; spares K+/H+
88
Describe the onset of action of spironolocatone.
Slow, takes days to have an effect
89
What are the adverse effects of spironolactone?
1. Hyperkalemia (most important)
2. Metabolic acidosis
3. Gynecomastia/amenorrhea/impotence/decreased libido
4. GI upset (peptic ulcers)
5. CNS effects (headache, fatigue, confusion)
90
What is eplerenone?
Competitive antagonist of aldosterone binding (more expensive, but not anti-androgen efects)
91
How does spironolactone cause metabolic acidosis?
By blocking aldosterone binding, Na+ and H+ channels are expressed less. This decreases the lumen negative potential and reduces the driving force for H+, which remains in the blood, leading to decreased pH.
92
What are the indications of spironolactone?
1. Primary hyperaldosteronism
2. Secondary hyperaldosteronism
3. Liver cirrhosis
4. Hypertension
93
What is the MOA of amiloride?
Blocks Na+ channels in the principal cells
94
Discuss the pharmacodynamics of amiloride.
Blocking Na+ influx decreases the driving force for K+ efflux, so K+ is spared
95
What is the half-life of amiloride?
21 hours
96
How does amiloride get into the tubules?
Secreted via the organic base transporter
97
What are the adverse effects of amiloride?
1. Hyperkalemia (exacerbated by NSAIDs)
2. GI upset (nausea, vomiting, diarrhea)
3. Muscle cramps
4. CNS effects (headache, dizziness, etc.)
98
How does amiloride cause hyperkalemia?
Blocking Na+ influx decreases the lumen negative potential and reduces K+ efflux
99
What are the clinical indications of amiloride?
1. Edema
2. Hypertension
3. Combined with other diuretics to reduce K+ loss
100
What is the MOA of triamterene?
Blocks Na+ channels in the principal cells
101
Discuss the pharmacodynamic of triamterene?
Blocking Na+ influx decreases the driving force for K+ efflux so K+ is spared; active form can precipitate and obstruct tubular flow
102
What is the half-life and relative potency of trimaterene to amiloride?
4 hours; 10x less potent
103
How does triamterene get into the tubules?
Secreted via the organic base transporter
104
What are 2 old ADH antagonists and what are kind of drugs are they?
1. Demeclocycline (tetracycline antibiotic)
2. Lithium (treatment of mania)
Both are nephrotoxic
105
What is the MOA of Tolvaptan?
ADH antagonism; elective antagonist of vasopressin V2 receptor; induces increased, dose-dependent production of dilute urine without altering electrolyte balance
106
How is Tolvaptan absorbed and what is its half-life?
Oral; 6-8 hours
107
What are the 3 V2 receptor antagonists?
Tolvaptan
Mozavaptan
Lixivaptan
108
What is the V1a and V2 receptor agonist?
Conivaptan
109
What are the adverse effects of ADH antagonists?
1. Hypernatremia
2. Thirst
3. Dry mouth
4. Hypotension
5. Dizziness
110
What are the indications of ADH antagonists?
1. SIADH
2. Euvolemic/hypervolemic hyponatremia
3. CHF
111
What is conivaptan used for?
IV formulation for the treatment of euvolemic hyponatremia
112
What are the potassium wasting diuretics?
CA inhibitors, loop agents, and thiazides
113
What are the 3 determinants of capillary filtration?
1. Hydrostatic pressure
2. Oncotic pressure
3. Capillary permeability
114
How does edema occur?
Increased capillary hydrostatic pressure with decreased plasma oncotic pressure; this setting favors filtration over absorption
115
What do diuretics do in the setting of edema?
Decrease capillary hydrostatic pressure and increase plasma oncotic pressure to favor absorption over filtration.
116
In renal disease, you can get a urinary loss of albumin - how does this lead to systemic edema?
Hypoalbuminemia alters starling forces
117
In renal disease, you can get a reduced GFR - how does this lead to systemic edema?
Reduced GFR leads to renal Na+ retention
118
In liver cirrhosis, you can get increased pressure in hepatic sinusoids - how does this lead to systemic edem?
This increased pressure causes exudation of fluid into the peritoneal cavity. In addition to causing ascites, this leads to plasma volume depletion. The RAA system is activated, leading to renal Na+ retention and edema. Note that hypoalbuminemia also leads to plasma volume depletion and its downstream effects.
119
Hepatic cirrhosis is resistant to ___, but this diuretic is effective.
Resistant to loop diuretics; aldosterone receptor antagonists are effective
120
How can heart disease lead to systemic edema?
In right ventricular dysfunction, hypotension leads to renal Na+ retention. Left ventricular dysfunction also leads to hypotension and its downstream effects. It also leads to increased pulmonary venous pressure and pulmonary edema.
121
Thiazide/loop diuretics can be effective in treating CHF, but they may cause what problem if aldosterone is high?
Excessive K+ loss, leading to hypokalemia. This can increase risk of coronary events, stroke, and sudden death
122
What is a good alternative diuretic to prevent hypokalemia-induced cardiac dysfunction in CHF?
Spironolactone, or combining ACE inhibitors with thiazide or loop diuretics (NEVER with spironolactone)
123
What drug is indicated in right heart failure?
Oral loop diuretics
124
What drugs i indicated in left heart failure (acute)/
IV loop diuretics
125
What is hyponatremia?
Serum Na+ concentration <136 mEg/L
126
What are the symptoms of hyponatremia?
Headache/disorientation, fatigue, hallucinations, respiratory arrest, seizures, coma, and death (CNS symptoms)
127
What are some causes of hypovolemic hyponatremia?
Diarrhea, vomiting, excessive sweating
128
What is an effective treatment for hypovolemic hyponatremia?
Infusion of 0.9% saline
129
What are some causes of euvolemic hyponatremia?
SIADH, hypothyroidism, adrenal insufficiency
130
Can a saline infusion be used to treat euvolemic hyponatremia?
No - it may be ineffective or worsen the hyponatremia
131
What are some causes of hypervolemic hyponatremia?
CHF, cirrhotic liver disease, nephrotic syndrome
132
Can a saline infusion be used to treat hypervolemic hyponatremia?
No
133
What drug has been shown to increase serum [Na+] and urine output while decreasing urine osmolality?
AVP receptor antagonists
134
For uncomplicated HT, what drug should be used?
Thiazide diuretic
135
What happens in nephrogenic diabetes insipidus?
Disruption of ADH effects leading to the inability to concentrate urine (leas to polyuria)
136
What can be used to treat nephrogenic diabetes insipidus?
Thiazides
137
Most kidney stones contain ___.
Calcium
138
Why are thiazides useful in some patients with calcium oxalate stones?
They decrease Ca2+ concentration by promoting reabsorption in the DCT
139
What is hypercalcemia?
Marked elevation of serum calcium >14 mg/dL
140
What causes hypercalcemia?
Malignancy or primary hyperparathyroidism
141
What are the symptoms of hypercalcemia?
Nausea, vomiting, alterations of mental status, abdominal/flank pain, constipation, lethargy, depression, weakness and vague aches, polyuria, headache, coma
142
What is used to treat hypercalcemia?
Loop diuretic with hydration; AVOID thiazide diuretics (would exacerbate)
143
What are some causes of diuretic resistance?
1. NSAID co-administration
2. CHF/chronic renal failure
3. Nephrotic syndrome
4. Hepatic cirrhosis
144
What do NSAIDs cause diuretic resistance
They block PG-induced increase in RBF (vasodilation). They increase expression of Na/K/2Cl cotransporter in TAL. Finally, they compete for organic acid transporter in PCT.
145
What is loop + thiazide combination therapy used for?
In patients refractory to one or the other (may be too robust and lead to K+ wasting)
146
What is K+ sparing + loop or thiazide combination therapy used for?
Prevention of hypokalemia (avoid in renal insufficiency)
