Block 2 - Diuretic Pharm

Question 1

How are diuretics classified?

Answer 1

1. Site of action (loop)
2. Efficacy (high-ceiling)
3. Chemical structure (thiazide)
4. Similarity of action with other diuretics (thiazide-like)
5. Effects on K+ excretion (K+ sparing)

Question 2

What is a nephron?

Answer 2

Single epithelium lined by a single layer of cells which can generically be referred to as tubular epithelial cells

Question 3

Describe the efficacy of diuretics working in the PCT?

Answer 3

PCT reabsorbs 65% of filtered Na+, however diuretics have limited effect

thick ascending limb has a great re-absorpative capacity -> reabsorbs most of the rejective from the PCT

Question 4

What is the MOA of CA-I?

Answer 4

NaHCO3 is poorly reabsorbed from the lumen -> needs to be converted to CO2 and H2O by CA that is inhibited by CAI located in the PCT

Question 5

How does CA-I effect renal system?

Answer 5

CAI decreases NaHCO3 reabsorption by increasing HCO3 excretion -> Increased urine pH -> Metabolic acidosis

Question 6

How does CA-I effect extra-renal system?

Answer 6

CA increases HCO3 in aqueous humor-> CAI decreases aqueous humor formation and intraocular pressure

Question 7

What are the therapeuti uses of CAIs?

Answer 7

Glaucoma, edema (low efficacy)

Question 8

What is an example of CAI? Its characteristics?

Answer 8

Diamox (Acetazolamide)
F: 100%
t1/2: 6-9 h
Can cause sulfa-like toxicities due to sulfonamide

Question 9

What is important about the thick ascending loop of henle (TAL)?

Answer 9

1. Site for reabsorption of Na, K, Cl but nearly impermeable to water
2. Major site of Ca2+ and Mg2+ reabsorption

Question 10

Why are loops considered high ceiling?

Answer 10

Highly efficacious diuretics

Question 11

How much Na+ does TAL reabsorb?

Answer 11

20%

Question 12

What is the NKCC2 and how do loops affect it?

Answer 12

1. NKCC2 carriers mediate reabsorption of Na, K, and 2Cl
2. Loops inhibit this carrier

Question 13

What are the loop diuretics?

Answer 13

1. Lasix (Furosemide)
2. Demadex (Torsemide)
3. Ethacrynic acid
4. Bumex (Bumetanide)

Question 14

PK properties of Lasix?

Answer 14

F ~ 60%
t½ ~ 1.5 h
CL (~65% renal ~35% hepatic)].

Question 15

PK properties of Demadex

Answer 15

F ~ 80%
t½ ~ 3.5 h
CL (~20% renal ~80% hepatic)].

Question 16

PK properties of Ethacrynic acid?

Answer 16

F ~ 100%
t½ ~ 1 h
CL (~67% renal ~37% hepatic

Question 17

PK properties of Bumex?

Answer 17

F ~ 80%
t½ ~ 0.8 h
CL (~62% renal ~38% hepatic)

Question 18

How do loops cause hyponatremia? Along with other ADRs?

Answer 18

↑ excretion of Na+, K+, Ca2+, Mg2+ with fluid volume depletion, hypokalemia, hypomagnesemia, and hypocalcemia

Question 19

How do loops cause hyperuricemia?

Answer 19

Decrease uric acid excretion that may result to gout like symptoms

Question 20

What are some non-renal loop actions?

Answer 20

Direct vascular effects, increasing systemic venous capacitance and decreases left ventricular filing pressure

Question 21

What loop diuretics have weak CAI activity?

Answer 21

Lasix and Ethacrynic acid

Question 22

What are loop diuretic indications?

Answer 22

1. CHF
2. HTN
3. Edema of CKD
4. Nephrotic syndrome
5. Ascites of liver cirrhosis
6. Acute pulmonary edema

Question 23

What are the ADR of loops?

Answer 23

1. Fluid and electrolyte imbalance
2. Gouty attacks
3. Hyperglycemia
4. Ototoxicity (hearing impairment/deafness)

Question 24

How much NaCl is reabsorbed in DCT? Water

Answer 24

10%
Impermeable to water

Question 25

What is the MOA of thiazides?

Answer 25

NCC (Na/Cl carrier) pumps Na+ and Cl- into DCT and benzothiadiazides inhibits this process located in the DCT

Question 26

What are the thiazide drugs?

Answer 26

1. Hydrochlorothiazide 2. Hygroton, Thalitone (Chlorthalidone) 3. Chlorothiazide 4. indapamide 5. Metolazone

Question 27

PK of hydrochlorothiazide?

Answer 27

F ~ 70% t½ ~ 2.5 h cleared renally

Question 28

PK of chlorthalidone?

Answer 28

F ~ 65% t½ ~ 47 h CL (~65% renal, ~ 10% biliary, ~25% unknown pathway

Question 29

PK of chlorothiazide?

Answer 29

F = 9 – 56% t½ ~ 1.5 h cleared renally

Question 30

PK of indapamide?

Answer 30

F ~ 93% t½ ~ 14 h cleared hepatically

Question 31

PK of metolazone?

Answer 31

F ~ 60% CL (~80% renal, ~10% hepatic, ~10% biliary

Question 32

What are some of the pharmacological actions of thiazides and how does that contribute to its ADRs?

Answer 32

1. Increased Na+ and Cl- excretion with volume depletion -> hyponatermia, hypochloremia, hypotension 2. Increase excretion of K+ -> hypokalemia 3. Decreased Ca+ and uric acid excretion -> hypercalcemia and hyperuricemia 4. Can cause weak CAI action

Question 33

What are the indications of thiazides?

Answer 33

1. HTN 2. Edema with CHF 3. Hepatic cirrhosis 4. Renal (nephrotic syndrome and chronic renal failure)

Question 34

What are common ADRs of thiazides?

Answer 34

1. Fluid and electrolyte balance 2. hypotension 3. hypokalemia, hyponatremia, hypochloremia 4. metabolic alkalosis 5. hypomagnesemia 6. hypercalcemia, and hyperuricemia

Question 35

How much of NaCl is reabsorbed in the CT?

Answer 35

2-5%

Question 36

What is important about the CT?

Answer 36

1. Site where aldosterone exerts a significant influence 2. Major site of potassium secretion

Question 37

What drug class is active in the CT?

Answer 37

K+ sparing

Question 38

What is the MOA of K+ sparing

Answer 38

Na+ is reabsorbed by epithelial Na+ channels (ENaC) with the loss of K+ and H+ Diuretic inhibits ENaC -> increased Na+ and Cl- excretion

Question 39

What are potassium sparing drugs?

Answer 39

1. Amiloride 2. Triamterene

Question 40

PK of amiloride?

Answer 40

F = 12 - 25% t½ ~ 9 h cleared renally

Question 41

PK of triamterene?

Answer 41

F ~ 50% t½ ~ 4 h extensively metabolized to an active metabolite which is cleared hepatically

Question 42

What is aldosterone antagonists site of action?

Answer 42

CT

Question 43

What are the aldosterone antagonists?

Answer 43

1. Spironolactone (Aldactone, CaroSpir) 2. Eplerenone

Question 44

PK of aldactone?

Answer 44

Some affinity toward progesterone and androgen receptors F ~ 65% t½ ~ 1.6 h cleared hepatically

Question 45

PK of eplerenone?

Answer 45

Very low affinity for progesterone and androgen receptors t½ ~ 5 h cleared hepatically

Question 46

ADRs of diuretics in the CT? Spironolactone?

Answer 46

Hyperkalemia Gynecomastia, impotence, menstrual irregularities

Question 47

In what ways are thiazides administered? Names?

Answer 47

Coadministered with thiazides and loops Dyazide, Maxzide (Triamterene + HCTZ) K+ sparing/thiazide

Question 48

How do loops and thiazide induce hyperuricemia?

Answer 48

1. Urate is poorly soluble and is transported across cell membranes 2. Diuretics increase rate reabsorption at the PCT and inhibit secretion into tubules by competing with irate for the efflux transporters

Question 49

According to the highlighted number which drugs correspond to hyper uricemia

Answer 49

2. Furosemide, bumetanide 3. Furosemide, thiazides 4. HCTZ, torasemide 5. Torasemide

Question 50

What is the BBW of loop diuretics?

Answer 50

Potent High doses may need to profound diuresisw with water and electrolyte depletion

Question 51

What is the BBW of HCTZ? Counseling points?

Answer 51

1. Increased risk of non-melanoma skin cancer Requires protection of skin from sun and undergo skin cancer screenings

Question 52

What is are the outcomes of chronic diuretic use?

Answer 52

Sustained deficit in total-body Na+ which is not compatible with life

Question 53

What is diuretic braking?

Answer 53

Renal compensatory mechanisms try to bring the balance of Na+ excretion with Na+ intake

Question 54

What is the mechanism of braking?

Answer 54

1. Activation of sympathetic nervous system 2. Activation of RAAS 3. Decreased arterial BP, renal epithelial cell hypertrophy 4. Increased renal epithelial transporter expression and alterations in natriuretic hormone (ANP)