Ellen - Pharmacology 2: Diuretics

Front 1

What are diuretics used for?

Back 1

used to correct abnormal ECF volumes and treat edema

Front 2

What urine changes are needed to treat diuretics?

Back 2

↑ urine volume
↑ urine Na+ content

Front 3

How does edema occur?

Back 3

Disease states → ↓blood flow to kidneys = sensed as insufficient arterial blood volume → salt & water retention = edema

Front 4

What disease states can lead to edema?

Back 4

CHF, cirrhosis, renal failure, etc

Front 5

What techniques are used to treat CHF? Types of drugs used to achieve this?

Back 5

treat the heart & use diuretics to ↓ afterload
thiazides, loop diuretics & aldosterone antagonists

Front 6

How is ascites from hepatic cirrhosis treated? What do you have to watch out for?

Back 6

thiazide, loop and K+ sparing diuretics
monitor plasma protein levels and altered drug availability

Front 7

What drugs are used in the treatment of pulmonary edema?

Back 7

Treat aggressively with loop diuretics

Front 8

What drugs are used in the treatment of cerebral edema?

Back 8

Osmotic diuretics for direct effects

Front 9

What drugs are used in the treatment of nephrotic syndrome?

Back 9

Treat with thiazide diuretics and ↓ salt intake

Front 10

What drugs are used in the treatment of acute renal failure?

Back 10

use osmotic or loop diuretics

Front 11

What's the primary goal in the treatment of renal edema?

Back 11

maintain kidney function

Front 12

What drugs are used in the treatment of chronic renal failure?

Back 12

treat aggressively with loop diuretics

Front 13

What diuretics are used in the treatment of hypertension?

Back 13

thiazides +/- K sparing
OR
loop + thiazides (if refractory)
AND ↓salt intake

Front 14

What diuretics are used in the treatment of Nephrolithiasis?

Back 14

thiazides to ↑ calcium reabsorption
↓ salt intake

Front 15

What diuretics are used in the treatment of Hypercalcemia?

Back 15

Loop diuretics to ↑ calcium excretion
Normal saline (to prevent contraction of extracellular space)
+/- K+ as needed

Front 16

What diuretics are used in the treatment of Nephrogenic Diabetes Insipidus?

Back 16

thiazide or loop diuretics to reduce plasma volume and contract the extracellular space

Front 17

What do all primary actions of diuretics involve?

Back 17

Changes in either secretion or reabsorption of solute in the nephron

Front 18

What drives/opposes filtration at the glomerulus?

Back 18

driven by hydrostatic pressure
opposed by oncotic pressure

Front 19

What plasma contents aren't filtered at the glomerulus?

Back 19

Cells
Proteins (and drugs bound to proteins)
Lipids

Front 20

What's the site of action for all diuretics? What are the exceptions?

Back 20

within the lumen of the nephron
Exceptions = the K+ sparing aldosterone antagonists, spironolactone and eplerenone

Front 21

Are diuretics filtered? What's the exception to this?

Back 21

No, they're bound to plasma proteins
Exception = aldosterone antagonists and the osmotic diuretics (mannitol)

Front 22

How are the unfiltered diuretics transported into the nephron?

Back 22

by organic acid (anion) & base (cation) transporters located in the proximal tubule

Front 23

Which conditions decrease access of diuretics ot the tubule lumen?

Back 23

↓ renal blood flow
↑ levels of other drugs transported by OA/B transporters

Front 24

What are some drugs that are also transported by the organic acid and base transporters?

Back 24

alpha-ketoglutarate
catecholamines
uric acid
choline
histamine
antibiotics
cimetidine
probenecid

Front 25

How much is reabsorbed with an isotonic filtrate?

Back 25

about 80%

Front 26

What determines the osmoticity of the medullary interstitum?

Back 26

The countercurrent mechanism = hyperosmotic

Front 27

How much of the fitrated load is reabsorbed by the loop of Henle?

Back 27

About 15% (can increase to up to 80%)

Front 28

What's the osmotic state of the thick ascending limb filtrate?
What can change this?

Back 28

Hypotonic
Loop diuretics = hypertonic

Front 29

How much of the fitrated load is reabsorbed by the DCT and cortical collecting duct?

Back 29

About 5%

Front 30

What drug affects the DCT and Cortical Collecting Duct? What's it's mechanism?

Back 30

Aldosterone acts at the nucleus of these cells to increase protein synthesis that increases Na permeability

Front 31

What affect does ADH have at the medulary collect duct?

Back 31

Causes aquaporins or H2O channels to fuse with the surface membrane, ultimately = concentrated, hypertonic urine

Front 32

Where does ADH work? What does it do?

Back 32

Medullary collecting duct.
Regulates H2O permiability

Front 33

What influences K+ loss?

Back 33

Secretion is increased by increased K or Na load or increase in pH. It is decreased by decreased pH

Front 34

What's K exchanged for at the distal nephron?

Back 34

Na
(same with H+)

Front 35

What can hypokalemia cause?

Back 35

ECG abnormalities
cardiac arrhythmias
muscular weakness
drowsiness
confusion
loss of sensation
↑ binding of cardiac glycosides

Front 36

What are two factors influencing diuretic effectiveness?

Back 36

1. the transport mechanism affected
2. where the diuretic acts in the nephron

Front 37

Why are proximally acting diuretics weak?

Back 37

even though 70-80% of the filtered load is handled, their actions are counteracted by more distal reabsorption mechanisms

Front 38

Why are distally acting diuretics weak?

Back 38

Because only 5-10% of the filtered load is involved

Front 39

Why are loop diuretics strong?

Back 39

1. An important transport mechanism (Na+,K+,2Cl- cotransporter) is inhibited
2. The affected site handles a large fraction of the filtered load (15-50%)
3. More distal mechanisms are not able to compensate

Front 40

What is required to produce concentrated urine?

Back 40

A hypertonic medullary interstitium

Front 41

How is a hypertonic medullary interstitium created?

Back 41

The loss of H2O and gain of Na+ in the descending limb of Henle
Reabsorption of Na+ w/o H2O in the ascending limb of Henle

Front 42

How is a hypotonic filtrate/dilute urine formed?

Back 42

Reabsorbing Na+ w/o H2O in the ascending limb of Henle and the distal convoluted tubule

Front 43

What's required to produce either a concentrated or dilute urine? What type of diuretics block this process?

Back 43

Reabsorption of Na+ w/o H2O in the ascending limb of Henle
Loop diuretics = impairs both concentration and dilution

Front 44

Do diuretics acting at distal to the loop of Henle (thiazides) influence dilution or concentration of urine?

Back 44

Only dilution

Front 45

What are the diuretic agents? (6)

Back 45

1. CA Inhibitors
2. Osmotic diuretics
3. Thiazides
3a. Thiazide-related
4. K+ sparing
5. Loop or high ceiling
6. Antidiuretics and ADH antagonists

Front 46

What's historically important about carbonic anhydrase inhibitors?

Back 46

Found by serendipity in 30's:
(1) led to discovery of carbonic anhydrase and its role in acid/base balance
(2) CA inhibitors were 1st orally active, non-mercurial diuretics

Front 47

Names of 2 Carbonic Anhydrase Inhibitors?

Back 47

acetozolamide, methazolamide

Front 48

Why do Carbonic Anhydrase Inhibitors have weak diuretic activity?

Back 48

1. Cause a self-limiting metabolic acidosis due to the loss of HCO3-
2. act at proximal tubule = effects reversed by more distal nephron

Front 49

How are Carbonic Anhydrase Inhibitors used as diuretics?

Back 49

used to produce an alkaline urine to trap & increase the loss of weak acids in urine = to reverse metabolic alkalosis due to other diuretics

Front 50

How are Carbonic Anhydrase Inhibitors used clinically (non-diuretic usage)? (5)

Back 50

1. glaucoma (↓ vitreous humor)
2. ↑ CNS pressure or altitude sickness (↓ CSF)
3. Epilepsy (↓ pH?)
4. Some types of hypokalemic periodic paralysis
5. Hyperphosphatemia (↑ urinary PO4 secretion)

Front 51

What are the adverse effects of Carbonic Anhydrase Inhibitors?

Back 51

drowsiness & dizziness
blood dyscrasias
skin reactions

Front 52

How do Carbonic Anhydrase Inhibitors reach their site of action?

Back 52

Organic acid transporter

Front 53

When are Carbonic Anhydrase Inhibitors contraindicated?

Back 53

Pts with liver cirrhosis can = hyperammonemia and hepatic encephalopathy

Front 54

Name 4 osmotic diuretics? Which is most often used?

Back 54

mannitol, urea, glycerin & isosorbide

mannitol

Front 55

Route for mannitol? Why?

Back 55

IV, can't be absorbed from the gut

Front 56

How do osmotic diuretics work?

Back 56

Osmotically active particles in the lumen = retention of H2O = ↑ [H2O] = ↓ [Na+] in the tubule lumen, ↓ driving force for reabsorption of Na+, ↑ H2O & some Na+ excretion in the urine

Front 57

Where do osmotic diuretics work?

Back 57

Act primarily at the proximal tubule & to a less extent at the ascending limb of Henle

Front 58

How is water retention related to osmotic diuretic quantity?

Back 58

Directly related - large amounts may be needed.

Front 59

What must osmotic diuretics be able to do to achieve large quantities?

Back 59

- be freely filtered at the glomerulus
- undergo limited reabsorption
- be pharmacologically and metabolically inert

Front 60

What types of diuretics can maintain urine volume and kidney function?

Back 60

Osmotic diuretics

Front 61

When are osmotic diuretics not useful?

Back 61

If there is severe renal damage and loss of the selective permeability of the renal tubule membrane (i.e. caused by nephrotoxic agents or renal ischemia)

Front 62

How are osmotic diuretics used (non-diuretically)?

Back 62

Used to treat:
↑ intracranial pressure (↓CSF)
↑ intraocular pressure (↓ aqueous humor)

Front 63

What are the adverse effects of osmotic diuretics?

Back 63

If given too rapidly IV, osmotic diuretics cause large shifts of fluid from cells to ECM = ↓ cell volume and impaired function

Front 64

When are osmotic diuretics contraindicated?

Back 64

CHF

Front 65

Name 3 Thiazides

Back 65

chlorothiazide, polythiazide, hydrochlorothiazide

Front 66

What type of medications are thiazides and how do they produce diuresis?

Back 66

Sulfonamide derivatives
Produce a diuresis with ↑ Cl- (not ↑ HCO3-) = effective in both acidic & alkaline conditions

Front 67

What happens with high concentrations of some thiazides?

Back 67

Inhibit CA = ↑ HCO3- loss

Front 68

How do thiazides differ?

Back 68

duration of action
extent of CA inhibition
maximally effective dose
binding to serum proteins

Front 69

How do thiazides enter the nephron? What effects can this have?

Back 69

Organic acid transporter
Interact with other compounds that use this transporter like penicillin and uric acid (competition can = ↑ serum uric acid)

Front 70

What's the mechanism of action for thiazides?

Back 70

Inhibition of Na & Cl- co-transport and reabsorption of these ions in the distal tubule

Front 71

What does the action of thiazides partly depend on?
What drug can inhibit thiazides under certain conditions?

Back 71

Increasing kidney prostaglandins

May be inhibited by NSAIDS

Front 72

What effects does thiazide-induced transporter inhibiton have on urine concentration?

Back 72

Increases Na, Cl, and, secondarily, K+.

Front 73

Are thiazides weak or strong diuretics? Why?

Back 73

Weak since only 5% of filtered Na is reabsorbed where they act.

Front 74

Why do thiazides produce less ECF distortion?

Back 74

Only cause modest diuresis and effect several ionic species

Front 75

What are the clinical uses of thiazides?

Back 75

Treat edema associated with: CHF, liver cirrhosis, premenstrual tension, and hormone therapy
Hypertension – actions involve direct effects on vascular smooth muscle

Front 76

What effects do thiazides have on GFR and serum uric acid?

Back 76

Decreased GFR (not good if pt has decreased renal function)

Increased plasma uric acid (due to direct transporter competition and general increase in reabsorption due to decreased ECF volume)

Front 77

What effects do thiazides have on Ca2+ and Cl excretion?

Back 77

↓ Ca2+ excretion – useful for hypercalciuria/osteoporosis

↑ Cl- excretion (and other halides, i.e. iodide(consider supplement) and Iodide/bromide/fluoride (treat toxicity)

Front 78

What are the adverse effects of thiazides? (6)

Back 78

↑ cholesterol (5-15% - transient) & Triglycerides
Hypokalemia w/ prolonged use
Arrhythmias in some settings
Hyperglycemia (bad for diabetics)
Metabolic alkalosis
Hyperuricemia

Front 79

How can thiazides cause hyponatremia?

Back 79

↑ ADH due to ↓ plasma volume
↓ diluting capacity of kidney
↑ thirst assoc with a ↓ plasma volume

Front 80

Name 3 thiazide-related drugs

Back 80

metolazone, chlorthalidone, indapamide

Front 81

How are thiazide-related drugs the same/different than thiazides?

Back 81

Chemically similar but don't inhibit CA
Uses and adverse effects are similar

Front 82

Efficacy, common combo med, and use of metolazone?

Back 82

Efficacious
Can be given in combination with a loop diuretic
Can be effective with renal insufficiency

Front 83

Special action and combo/use of indapamide?

Back 83

Has antihypertensive actions independent of diuretic activity
Used with loop diuretics in cases of renal failure

Front 84

What are the two types of K+ sparing diuretics?

Back 84

Aldosterone antagonists

Nonaldosterone antagonists

Front 85

What is spironolactone?

Back 85

An aldosterone antagonist that's a
structural analog of aldosterone

Front 86

What's the active metabolite of spironolactone? How is it formed?

Back 86

canrenone
1st pass metabolism in the liver

Front 87

What is the mechanism of action for spironolactone?

Back 87

It's active metabolite canrenone competes with aldosterone for binding to its cytoplasmic receptor & inhibits its actions

Front 88

When is spironolactone ineffective?

Back 88

Adrenalectomized pts (requires aldosterone to have effects)

Front 89

What type of inhibition is induced by spironolactone?

Back 89

competitive (effects reversed by increased aldosterone)

Front 90

What is eplerenone?

Back 90

an analog of spironolactone that is more selective for the aldosterone receptor

Front 91

What are the clinical uses of Aldosterone antagonists? (4) (why?)

Back 91

1. Primary and secondary hyperaldosteronism
2. Hypokalemia: given with other diuretics used to tx HTN/CHF
3. CHF: spironolactone found to have significant benefit independent of its diuretic effects
4. Liver cirrhosis & Nephrotic syndrome to avoid excessive loss of K+

Front 92

What are the adverse effects of Aldosterone antagonists? (6)

Back 92

1. hyperkalemia
2. ↑ serum Li+
3. ↓ metabolism cardiac glycosides
4. gynecomastia (reversible)
5. tumorgenic in rats
6. hyperchloremic metabolic acidosis (due to ↓ H+ secretion)

Front 93

Name 2 Nonaldosterone antagonists.

Back 93

triamterene
amiloride

Front 94

Nonaldosterone antagonists mechanism of action?

Back 94

↓ Na+ reabsorption in the distal nephron by ↓ Na+ permeability = ↓ K+ loss.
Inhibition of Na+/H+ exchange = ↓ loss of NH4+

Front 95

Clinical uses of nonaldosterone antagonists?

Back 95

Used in combination with other diuretics to ↓ K+ loss when treating edemas associated with CHF, cirrhosis, etc.

Front 96

Clinical use of Amiloride?

Back 96

Has antihypertensive effects that are additive with those of the thiazides

Front 97

Adverse effects of nonaldosterone antagonists?

Back 97

Hyperkalemia (need to monitor serum K+ due to: electrical disturbances and ↓ effects of cardiac glycosides)

Front 98

Adverse effects of Triamterene? (3)

Back 98

- ↑ serum uric acid & ↑ chance of gout
- inhibits dihydrofolate reductase = megaloblastic anemia w/ cirrhotic pts
- low solubility, can precipitate in urine and cause stones

Front 99

Name four loop/high ceiling diuretics.

Back 99

ethacrynic acid
furosemide
bumetamide
torsemide

Front 100

Effectiveness of loop/high ceiling diuretics? Percent Na+ excretion?

Back 100

Most effective
Can = 20%+ filtered Na+ excretion

Front 101

Mechanism of action for loop/high ceiling diuretics?

Back 101

Primary is inhibition of the Na+/K+/2 Cl- transporter in the thick ascending limb of Henle
(20-50% of the filtered Na+ is handled at this site and the more distal nephron cannot compensate)

Front 102

Concentration effects of loop/high ceiling diuretics?

Back 102

Transporter block = ↓ hyperosmolarity in the medullary interstitutium = impairs ability to produce dilute and concentrated urine.
Also, ↑ loss of K+ and H+ due to ↑ Na+ load at distal nephron and ↓ positive potential in lumen = ↑ excretion of Ca2+ and Mg2+

Front 103

What drug may decrease the actions of loop/high ceiling diuretics? Why?

Back 103

NSAIDS = decreased prostaglandin synthesis.
Loop diuretics may increase prostaglandins which may produce part of their effects.

Front 104

What do loop/high ceiling diuretics change the excretion of?

Back 104

↑ plasma uric acid
↑ excretion of Ca2+ & Mg2+ (can treat hypercalcemia)
↑ excretion of titratable acid & NH4+ (= metabolic alkalosis)

Front 105

What can high doses of furosemide & bumetamide cause?

Back 105

They can inhibit CA = ↑ excretion of HCO3-

Front 106

What other ions do loop/high ceiling diuretics increase the excretion of? Clinical use of this?

Back 106

Monovalent anions (Cl, Br, I, F)

Used to tx toxicities

Front 107

Which diuretic increases renal blood flow?

Back 107

fuorsemide

Front 108

Which diuretics decrease pulmonary congestion in CHF?

Back 108

fuorsemide
ethacrynic acid

Front 109

What actions can loop diuretics have that are independent of diuretic activity?

Back 109

can increase blood flow through vascular beds

Front 110

How do loop diuretics access the tubule lumen?

Back 110

Bind plasma proteins and enter via the organic acid transporter

Front 111

When should you consider using a higher dose of loop diuretics?

Back 111

OA competing compounds (NSAIDS, probenecid)
Renal disease

Front 112

Clinical uses of loop diuretics? (7)

Back 112

1. Acute pulmonary edema ER
2. Edema: of cardiac, hepatic or renal origin (esp if refractory to less efficacious diuretics)
3. Mild to moderate HTN
4. Acute Hypercalcemia
5. Hyperkalemia (give w/ Na+ and H2O)
6. Acute renal failure (to ↑ urine flow and K+ excretion)
7. Anion overdose (bromide, fluoride and iodide toxicities, give with saline solution)

Front 113

Which diuretic can decrease blood pressure w/o diuresis?

Back 113

Torsemide
(also indapamide and thiazides)

Front 114

Adverse effects of loop diuretics? (3)

Back 114

1. Hypokalemia (must monitor K+ levels)
2. Metabolic Alkalosis
3. Extreme diuresis = volume depletion, hypotension & orthostatics, dizziness, h/a

Front 115

What patients should be really concernted about the hypokalemic effects of loop diuretics?

Back 115

Patients on digitalis

Front 116

What adverse effects are caused from competition for binding to organic acid transporter while on loop diuretics? What meds are involved?

Back 116

↑ nephrotoxicity with cephalosporins
↑ ototoxicity with aminoglycoside antibiotics
↑ salicylate toxicity

Front 117

What adverse effects do loop diuretics have on hearing and blood sugars?

Back 117

Ototoxicity & transient deafness
Diabetogenic (furosemide & bumetamide)

Front 118

What adverse effects do loop diuretics have due to competitive binding of serum proteins?

Back 118

Messes up kinetics of warfarin and clofibrate

Front 119

What adverse effects do loop diuretics have on Li+?

Back 119

Decreased clearance

Front 120

What adverse effects do loop diuretics have on cholesterol?

Back 120

Increased LDL and TG levels

Front 121

What adverse effects do loop diuretics have on uric acid and magnesium? (why?)

Back 121

Hyperuricemia (due to increased reabsorption of uric acid in proximal tubule caused by decreased vascular volume)
Hypomagnesemia

Front 122

What adverse effects do loop diuretics have on vascular volume? What can this cause?

Back 122

Severe decrease
Can = hyponatremia if patients increase H2O intake due to hypovolemia-induced thirst

Front 123

What can you do when patients become refractory to normal doses of loop diuretics?

Back 123

Give in combo with thiazide/thiazide-related diuretcs to exhibit greater than additive effects (even when either drug alone only has min effects)

Front 124

What is the urinary issue in diabetes insiptidus? How can this be addressed?

Back 124

Polyuria due to ↓ADH
Can be treated (paradoxically) with thiazides/loop diuretics, which cause salt depletion and contraction of ECF = ↑ proximal tubule reabsorption of Na+ = ↓ volume of fluid reaching distal tubule

Front 125

What's the cause of Central diabetes insipidus? How's it treated? (2 drugs besides diuretics)

Back 125

↓ ADH levels
1. Arginine vasopressin (AVP = ADH) and analogs desmopressin and lypressin (IM, SC or intranasally)
2. Chlorpropamide (a sulfonylurea, which ↑ actions of ADH)

Front 126

What's the cause of nephrogenic diabetes insipidus? How's it treated? (2 drugs besides diuretics)

Back 126

↓ responsiveness to ADH
1. Amiloride to block Li+ uptake (if Li+ is involved in causing the decreased response)
2. NSAIDS, i.e. indomethacin (↓ prostaglandin synthesis = ↑ response to ADH)

Front 127

What's SIADH?

Back 127

Syndrome of inappropriate secretion of ADH = too much ADH

Front 128

How's SIADH treated? (4 drugs - how do they work?)

Back 128

1. Loop diuretics (↓ ability to concentrate the urine)
2. Demeclocycline (a tetracycline ↓ actions of ADH, can’t use with liver dysfunction)
3. Vaptans (nonpeptide V2 receptor antagonists - have shown promise in clinical trials. Approved = conivaptan)
4. Lithium (↓ ADH actions - not used because it's often ineffective and can cause kidney damage)