Diuretics And Aquaretics--Bahouth

Front 1

What are the categories of drugs that act predominantly in the proximal convoluted tubule?

Back 1

C.A. inhibitors
Osmotic diuretics
Loop diuretics

Front 2

Name a C.A. inhibitor:

Back 2

Acetazolamide

Front 3

Name an osmotic diuretic:

Back 3

Mannitol

Front 4

Name the three LOOP DIURETICS:

Back 4

Furosemide
Bumentanide
Torsemide

Front 5

Name eight diuretics that act predominantly in the distal convoluted tubule:

Back 5

Hydrochlorothiazide
Metolazone
Spironolactone
Amiloride
Chlorthalidone
Eplrenerone
Triamterine

Front 6

Name two drugs that act on collecting ducts by V2R agonism:

Back 6

Arginine vasopressin
Desmopressin (DDAVP)

Front 7

Name two drugs that act on collecting ducts by V2R antagonism:

Back 7

Conivaptan
Tolvaptan

Front 8

Identify where AQP-1 and AQP-2 is located.
What does this indicate?

Back 8

Only places that are permeable to water.

Front 9

Carbonic anhydrase inhibitors:
Mechanism of action.
Drug

Back 9

Inhibit C.A. --> bicarbonate loss in the urine
Acetazolamide

Front 10

CA Inhibitor:
Net effect

Back 10

Alkaline urine (from Na-bicarbonate loss in urine)
Enhanced chloride reabsorption --> acidosis

Front 11

CA inhibitor:
Clinical uses

Back 11

Diuretics: limited use
Alkalinize urine (Cysteinurea)
Reduce intra ocular pressure
Seizure management
Prophylaxis for mountain sickness

Front 12

Side effects of CA inhibitors:

Back 12

Metabolic acidosis
Greatly increased K+ loss in urine (acute effect)

Front 13

Review this slide and think about how CA inhibitors work.

What happens to pH of urine in carbonate loss?
What happens when more chloride is reabsorbed?

Back 13

Alkalinizes the urine.
For Cl- think HCl = acidosis

Front 14

What are the characteristics of osmotic diuretics?

Back 14

Small molecules that are filtered, but not reabsorbed by the kidney.

Front 15

What is the minor mechanism of action of osmotic diuretics?

Back 15

Osmotically inhibit Na+ and H20 reabsorption

Front 16

What is the major mechanism of action of osmotic diuretics?

Back 16

Large doses --> increase plasma osmolarity

1. Extract water from peripheral tissues and decrease blood viscosity
2. increase in medullary renal blood flow and reduce its tonicity.
3. Impair water reabsorption by thin descending limb of Henle's loop (depends on tonicity difference).
4. Impair NaCl and urea extraction by THIN ASCENDING limb of Henle's loop.
5. Interfere with transport processes in the TALH.

Front 17

What is the net effect of osmotic diuretics?
Name a drug.

Back 17

Significantly increase urine with small increments in NaCl and other ions.

Mannitol (injection) = ONLY DRUG TO KNOW FOR OSMOTIC DIURETICS

Front 18

When are osmotic diuretics used?

Back 18

Treatment of dialysis disequilibrium syndrome
Reduce intracranial pressure (from severe head trauma)
Reduce intraocular pressure

Front 19

What is a side effect of osmotic diuretics? What patients are they contraindicated in?

Back 19

Volume overload
Contraindicated in cardiac failure.

Front 20

What is the MOA of loop diuretics?
What does this causes (macula densa)? What is stimulated? What is increased? What is maintained?

Why are they called "high ceiling?"

Back 20

Inhibit Na-K-2Cl symporter in TALH (K+ must seep out).
Inhibit the ability of macula densa to "sense" NaCl.
Stimulated biosynthesis of prostaglandins. Increase in total renal blood flow. Maintain GFR.

Loss of sodium and water in urine due to inhibition of TALH Na+ reabsorption

Front 21

How do loop diuretics potently increase renin release?

Back 21

1. Inhibition of macula densa
2. Reflexively activate sympathetic NS
3. Stimulation of intrarenal baroreceptor mechanisms.

Front 22

What are the 5 net effects of loop diuretics (high-ceiling diuretics)?

Back 22

1. Mobilize NaCl (most potent class of diuretics that does this).
2. Copious diuresis and significant NaCl loss.
3. Increase urinary excretion of K+/H+
4. Increase excretion of Ca2+ and Mg2+
5. Impair ability of kidney to concentrate urine.

Front 23

What four clinical situations require the use of loop diuretics?

Back 23

1. Edema (cardia, hepatic, or renal origina)
2. Pulmonary edema
3. Hypercalcemia (to mobilize Ca2+)
4. Protect against renal failure

Front 24

How do loop diuretics help with pulmonary edema?

Back 24

1. Decrease pulmonary wedge pressure
2. Increase compliance of pulmonary vessels
3. Increase peripheral vascular capacitance
4. Reduce left ventricular filling pressure
5. Cause brisk diuresis

Front 25

What is one specific example of a loop diuretic (the common one)? Where does it act? How is it administered? What is it secreted by?

Back 25

Furosemide

Sulfonamide drug that inhibits NaCl reabsorption in TALH (oral and IV/IM)

Secreted by organic acid transporter to inhibit luminal symporter.

Front 26

True or false. Furosemide has a wide margin of safety.
Describe the dose response curve of furosemide that is influenced by renal disease. Why?

Back 26

True.
Due to impaired secretion of the drug.

Front 27

What are the five pharmacological effects of furosemide?

Back 27

1. Copious diuresis with significant NaCl losses.
2. Increased urinary excretion of K+/H+
3. Increased urinary excretion of Ca2+ and Mg2+
4. Increased renal prostaglandins
5. Increased venous capacitance

Front 28

How is furosemide administered?
How long until a diuretic response? How long does it last?
What is the half life? What is the drug bound to?
How much of drug is excreted in urine?

Back 28

Orally OD or BID
30 minutes until response --> lasts 8 hours
1.5 hours (short), extensively protein bound
65% excreted in urine

HIGH MARGIN OF SAFETY!

Front 29

What are the 3 major side effects of furosemide?

Back 29

1. Fluid/electrolyte abnormalities (hypokalemia and alkalosis) --> requires initial monitoring

2. Elevated BUN, hyperglycemia, hyperuricemia

3. Ototoxicity, sialadentitis (inflammation of salivary glands)

Front 30

What are common drug interactions of furosemide?

Back 30

1. Lithium
2. Indomethacin
3. Probenecid
4. Warfarin

Front 31

Which loop diuretic is forty times more potent than furosemide? Why would you ever use it?

Back 31

Bumentanide --> use instead of furosemide if patients are receiving warfarin

Front 32

Which loop diuretic also lowers BP? Anything special about its half life?

Back 32

Torsemide --> much longer half-life than other loop diuretics, so just given once daily.

Front 33

What are the three big segments of the distal convoluted tubule and collecting ducts?

Back 33

1. Na+-K+ aldosterone independent segment (Na-Cl symporter).

2. Aldosterone sensitive segment.

3. Sodium load segment.

Front 34

What two types of Na+ channels are expressed in IMCD?

Back 34

1. Amilioride sensitive cyclic nucleotide gated cation (CNG) channel.

2. Low conductance highly selective Na+ ENaC channel.

Front 35

What is the mechanism of action thiazide diuretics?
BENZOTHIADIAZIDES

Back 35

Inhibit NaCl reabsorption in the Na-K aldosterone independent segment of the distal tubule.

Front 36

What are the six pharmacologic effects of thiazide diuretics?

Big difference between thiazide and loop**

Back 36

1. Moderate loss of Na+, K+, and Cl- and causes a 3X increase in urine flow.
2. Serum loss --> reduced GFR (chronic)
3. Elevation of urinary potassium (hypokalemia)
4. Increased delivery of Na+ to distal tubule --> increased excretion of titratable acid.
5. Decrease urinary excretion of Ca2+.**
6. Increase urinary excretion of Mg2+.

Front 37

What are the three important uses of thiazide diuretic?

Back 37

1. Diuretic = reduce edema with CHF, cirrhosis, and nephrotic syndrome
2. Hypercalciurea and renal calcium stones.
3. Nephrogenic diabetes insipidus.
4. Osteoporosis (think calcium).

Front 38

When are most thiazides ineffective (GFR)?

Do thiazides require excretion into tubular fluid to exert effect like loop diuretics?

Back 38

GFR < 30-40 mL/min except for metolazone or indapamide

Yes!

Front 39

What are the two classes of thiazide diuretics? When do you use which?

Back 39

Class 1 = if GFR > 50 mL/min

Class 2 = more potent, use if GFR >30 and <50

Front 40

What are three examples of class I diuretics?

Which has the shortest half life?

Back 40

Hydrochlorothiazide (2.5 hour half life)
Chlorthalidone
Quinethazone

Front 41

What are two examples of class II thiazides? Which is the most potent?

Back 41

Metolazone (10x more potent than HCTZ)
Indapamide (20X more potent than HCTZ)

Front 42

What are four adverse reactions of thiazides?

Back 42

Deletion phenomena
Retention phenomena
Metabolic changes
Hypersensitivity and others

Front 43

Examples of the deletion phenomena?

Back 43

HyPOkalemia, hyPOchloremic alkalosis, hyPOmagnesemia, dilutional hyPOnatremia

Front 44

What are two examples of the retention phenomena?

Back 44

hyPERuricemia
hyPERcalcemia

Front 45

What are three examples of metabolic changes?

Back 45

hyPERglycemia
hyPERlipidemia
hyPERsecretion of renin and aldosterone

Front 46

What are some "hypersensitivity and other" reactions?

Back 46

Fever, rash, purpura
Pancreatitis
Sialadentitis
Withdrawal edema

Front 47

Between thiazides and loop diuretics, which has the higher NaCl excreted per dose?

Back 47

Front 48

What two types of cells are in the late DCT and CD?
What are the two principal cell types? What is each involved in? How is each regulated?

What happens when Na+ channel is inhibited?

Back 48

Principal and intercalated cells

Type A (Na+ reabsorption, K+ secretion --> hormonally regulated by aldosterone)
Type B (Na + reabsorption, K+ secretion --> load dependent regulation --> the more Na+ delivered, the more absorbed in exchange for K secretion)

Increase Na+ excretion, reduce K+ secretion.

Front 49

What is the physiological action of aldosterone (pathway)?

Back 49

Binds to receptor in DCT --> moves to nucleus, binds to HORMONE sensitive elements --> regulation of aldosterone-incuded EnaC Na+ channels --> enhanced transepithelial NaCl transport --> increase of lumen-negative transepithelial voltage --> increase in K+ secretion and H+ secretion.

Front 50

What is the mechanism of action of aldosterone antagonists?

Back 50

1. Bind aldosterone receptor in cytoplasm and prevents translocation to nucleus.
2. Reduce Enac channels that are involved in Na+ reabsorption.

Front 51

What is the net effect of aldosterone antagonists?

Back 51

1. Increase urinary excretion of Na+ (NATRIURETIC)
2. Inhibition of secretion of K+ and H+ (K-sparring)

Front 52

Give an example of an aldosterone antagonist.
Is this a prodrug that is extensively metabolized?
Which drug is an active metabolite with a longer half-life?

Back 52

Spironolactone. Yes
Canrenone

Front 53

What are the side effects of aldosterone antagonists?
How do you protect against hyperkalemia?

Back 53

Hyperkalemia (combine with thiazide)
Gynecomastia, hirsutism, uterine bleeding

Front 54

What are the clinical uses of aldosterone antagonists?

Back 54

Diuretics (in combination with HCTZ)
Used to treat CHF and cirrhosis.

Front 55

What are some examples of organic bases not structurally related to aldosterone (K-sparing diuretics)?

Back 55

Triamterene, amiloride

Front 56

What is their mechanism of action?

Back 56

Inhibit Na reabsorption in late distal tubule (sodium load segment).

Front 57

What are the pharmacological effects of triamterene and amiloride (k-sparing diuretics)?

Back 57

Increase urinary excretion of Na+ (weak effect)
Inhibit secretion of K+ and H+ (K-sparing)

Front 58

What are the clinical uses of K-sparing diuretics?
Side effects?

Back 58

Diuretics --> combinted with HCTZ to increase effectiveness and decrease K+ excretion

Hyperkalemia
Megaloblastic anemia in patients with cirrhosis

Front 59

What are the four types of atrial natriuretic peptide? Where is each found? Response of each?

Back 59

ANP, BNP = produced by heart in response to stretch
CNP = endothelial and renal origin
Urodilantin = found in urine, paracrine regulator of Na+ transport

Front 60

MOA of ANP?
MOA of BNP?

Back 60

ANP = atrial peptide produced in response to stretch --> binds NP receptor A (NPR) --> GC activated --> increase cGMP

BNP = produced by ventricle --> binds NPR-A similar to ANP

Front 61

MOA of CNP?

Back 61

Binds NPR-B in vascular smooth muscle cells and mediates relaxation.

Front 62

MOA of urodilatin?

Back 62

Arises from same precursor of ANP. Binds with low affinity to ANP-B in the glomeruli and IMCD.

Front 63

What is an example urodilatin? What are its clinical effects?

Back 63

Nesiritide
Increases Na+ excretion by inhibiting CNG nonspecific cation channel in IMCD and by inhibiting the renin angiotensin system and endothelial production.

Front 64

Why is nesiritide usefeul in CHF? Three things.

Back 64

1. Decreases systemic vascular resistance
2. Decreases left ventricular filling pressure
3. Increases cardiac output.

(no data that it actually reduces mortality though)

Front 65

What are the side effects of nesiritide?

Back 65

Numerous due to narrow therapeutic window

Front 66

What are the best tolerated drugs for the monotherapy of hypertension? Which have been demonstrated to decrease mortality in hypertension patients? Responses to diuretics are seen at lower or higher doses?

Back 66

Diuretics and ACEIs
Diuretics (alone or in combo with beta blockers)
Low = should avoid high due to side effects

Front 67

What are thiazides mostly used for? What is the most popular drug for therapy of high BP? Which drugs are effective in patients with impaired renal function when thiazides are not? When are these drugs ineffective?

Back 67

Mild-->moderate HT
HCTZ
Metolazone and indapamide (not effective when GFR <30 or creatinine > 2.5 mg/dL

Front 68

Which type of HT patients show a better response to thiazides? What would a poor response reflect?

What is the best way to administer HCTZ?

Back 68

"Volume dependent" HT (low renin levels)

High load of dietary sodium or impaired renal capacity to excrete sodium

Single morning dose (sustained effect, reduces K+ wastage during nighttime).

Front 69

When are loop diuretics used? Is more frequent monitoring required? How are these diuretics administered and when?

Back 69

Severe HT unresponsive to thiazides, renal insufficiency, cardiac failure, cirrhosis

Yes = can have more serious side effects
IV in HT crisis or acute pulmonary edema

Front 70

Administration of what is a common preventable causes of diuretic resistance. Why?

Back 70

NSAID

Prostaglandins --> reduce Na+ reabsorption, antagonist ADH, and distribute renal blood from cortex to the juxtaglomerulus

Front 71

What is useful to use in patients at risk of K+ depletion or in patients with hyperuricemia? What is the drug of choice in cirrhosis? What do you do if GFR is less than 50 mL/min? When are they contraindicated?

Back 71

K+ sparing diuretic
Spironolactone (add a loop diuretic)

Significant renal insufficiency (GFR < 75) or other K+ retaining conditions

Front 72

Where is ADH synthesized?

Back 72

Paraventricular and supraoptic nuclei of hypothalamus

Front 73

When is ADH released?

Back 73

1. Plasma osmolarity > 280 mOsm/Kg
2. Depletion of extracellular volume
3. Pain, nausea, hypoxia

Front 74

Where is the V1 receptor found (ADH receptor)? What is the result of binding?

Back 74

Vascular smooth muscle

Activation of Gq-PLC-IP3 pathway --> mobilization of Ca2+ --> vasoconstriction

Front 75

Where is the V2 receptor located? What happens upon binding?

Back 75

Principal cells in renal collecting ducts

Gs-cAMP, PKA activated --> increase rate of insertion of water channel containing vesicles (WCVs) into the apical membrane of CD.
PKA --> phosphorylates AQP-2 --> inserted as tetramers into apical membrane --> increase permeability of CD to water.
PKA --> phosphorylates urea transporter (VRUT or UT1) --> increased permeability of CD to urea.

Front 76

What is the net effect of ADH?

Back 76

Concentrates urine up to four times the osmolarity of plasma.

Front 77

What are aquaretics? What does activation of V1R cause?

Back 77

Synthetic peptides that are V1 receptor antagonists (ANTI-DIURETICS).
Activation of V1R --> GI and vascular smooth muscle contraction.

Front 78

What are the clinical uses of V1R agonists?

Back 78

IV to treat:
Post oprative ileus
Reduce bleeding in esophageal varices
Reduce bleeding during acute hemorrhagic gastritis

Front 79

What are examples of aquaretics?

Back 79

8-arginine vasopressin (discontinued due to side effects)
Terlipressin (fewer side effects)

Front 80

What are the two types of diabetes insipidus? Symptoms?

Back 80

1. Inadequate AVP secretion (central DI)
2. Insufficient kidney AVP response (nephrogenic DI)

Symptoms: excrete large amounts of urine, drink a lot of water (polydipsia)

Front 81

How do you distinguish central DI from nephrogenic DI?

Back 81

Administration of V2R agonist (desmopressin) --> will increase urine osmolarity in patients with central DI but no nephrogenic DI

Front 82

What are some causes of central DI?

Back 82

Acquired:
Head trauma, surgery or trauma in pituitary or hypothalamus, tumors, CNS ischemia (think head problems)

Genetic:
Autosomal dominant (chrom 20) --> loss of AVP

Front 83

How do you treat central DI?

Back 83

Synthetic vasopressin peptides: selective V2R agonists

Front 84

How is DDAVP (desmopressin) administered? What is it also used in?

Back 84

Nasally, IV, or oral.
Bleeding disorders, nocturnal enurisis (bed wetting in children)

Front 85

What are some causes of nephrogenic DI?

Back 85

Acquired:
Obstructive renal disease, drugs: Li, clozapine

Genetic:
X-linked gene encoding V2R --> frameshift, truncated receptor, or single amino acid mutation

Front 86

How do you treat nephrogenic DI?

Back 86

Maintain adequate water intake
Thiazide diuretics (may reduce polyuria by 50%)
--mild depletion of EC water and sodium --> compensatory mechanisms increase reabsorbative capacities of PCT --> reduce volume delivered to distal

Front 87

What is SIADH?

Back 87

Too much ADH produced --> impaired water excretion and plasma hypoosmolarity (HYPONATREMIA)

Front 88

What are the three drug classes associated with SIADH?

Back 88

Psychotropics (SSRI, haloperidol, tricyclic antidepressants)
Sulfonylureas: chloropropamide
Vinca alkaloids: vincristine, vinblastine

Front 89

What do you use to treat SIADH and hyponatremia?

Back 89

1. Water restriction, IV hypertonic saline
2. Loop diuretics
3. Demeclocycline: antagonizes ADH at V2 receptors
4. Vaptans

Front 90

What are some other water-retaining conditions? Pathways?

Back 90

CHF, cirrhosis, nephrotic syndrome --> reduction of effective blood volume --> hypovolemia exacerbated by diuretics --> AVP release --> hyponatremia

Front 91

What are vaptans? Give an example? Why is it a good choice for treatment of SIADH and hyponatremia?

Back 91

Selective V2R antagonist
Tolvaptan
29X more selective for V2R than V1aR

Front 92

What are the indications for tolvaptan? When is it used (hospital or at home)?

Back 92

SIGNIFICANT hypervolumemic and euvolemic hyponatremia (less than 15 mEq/L)
Symptomatic hyponatremia that resists correction with fluid retention

USED ONLY IN A HOSPITAL SETTING!!

Front 93

What is the metabolism of Tolvaptan (cyp?)
Side effects?

Back 93

CYP3
Hyperglycemia, GI disturbances, and clotting problems

Front 94

Which V2R antagonist is less selective than Tolvaptan? How is it given? Metabolism? Side effects?

Back 94

Conivaptan = IV for acute treatment of hyponatremia in hospital setting.
Metabolized by CYP3A4
Numerous = infusion site reaction

Front 95

What are the two types of aquaretics?

Back 95

V1a selective antagonist
V1b selective antagonist

Front 96

Where are the nephron sites of action of diuretics?

Back 96

Front 97

Look at review slides in lecture.

Back 97

Look at review slides in lecture.