THERAPEUTICS EX4 L11 (DIURETICS MEDCHEM) (FENG CHENG)

Describe osmosis

Diffusion of water through a selectively permeable membrane

How does water move during osmosis?

Moves from area of low solute concentration to high solute concentration

Describe osmotic equilibrium

Movement of water ceases; concentrations equal on both sides of the membrane

Formula for osmotic pressure?

pi = iMRT

i = van't Hoff factor

M=molarity

R = ideal gas constant (0.0821 Latm/molK)

T = temperature in K

How can diuretics affect osmosis?

Keep ion concentration high in urine

Disrupt osmosis

T/F: The kidney regulates ion conc. & urine volume by active reabsorption or secretion of ions &/or passive reabsorption of H2O.

True

The nephrons segments are divided... how?

Structurally and functionally into several segments

Each kidney has about how many nephrons?

1.2 million

T/F: Diuretics increase the volume of produced urine by acting on different parts of the nephron.

True

Where do acetazolamide/canagliflozin act in the nephron?

At the NaHCo3 Na-glucose co-transporter in the proximal convoluted tubule

Where do osmotic agents (like mannitol) act in the nephron? (three areas)

Proximal convoluted tubule

Descending loop of Henle

Collecting duct

Where do loop agents (like furosemide) act in the nephron?

Ascending loop of Henle (thick ascending limb, impermeable to water)

T/F: Diuretics increase the osmotic pressure in the kidneys, and cause water to leave blood into the forming urine.

True

T/F: Diuretics act primarily by increasing reabsorption of ions in the nephron.

False; diuretics act primarily by blocking reabsorption of ions in the nephron.

Where do thiazides act in the nephron? (two places)

Potentially descending loop of Henle

Primarily distal convoluted tubule (promote sodium excretion)

Where do aldosterone antagonists work in the nephron?

Collecting tubule/duct

Normal GFR?

~120 mL/min

Normal urine production?

~1mL/min or ~1.5L/day

About what percentage of tubular fluid is reabsorbed?

99%

Where do ADH (anti-diuretic hormone) antagonists work in the nephron?

Collecting duct

Where does adenosine work in the nephron? (3 places)

Proximal convoluted tubule

Ascending loop of Henle (thick ascending limb)

Collecting duct

Water permeability of the PCT is ______

A. Low

B. High

C. Very high

B is an acceptable answer

T/F: Diuretics are secreted from the proximal tubule to urine.

True

T/F: Polar molecules can cross the membrane in the PCT easily.

False; generally, polar molecules have a hard time crossing the membrane.

Ions are ________ molecules

A. Polar

B. Non-polar

A. Polar

What ions are most relevant to diuretic action?

NaHCO3

NaCl

Transporters in the luminal membrane?

Na+/H+ exchanger (NHE3)

Na+/Glucose transporter (SGLT2)

Cl-/Base- antiporter

Carbonic anhydrase (CA)

Transporters in the basolateral membrane?

Na+/K+ ATPase

Na+/HCO3- porter

Role of carbonic anhydrase in the lumen-urine?

Assist in dissociation of H2CO3 into H2O and CO2

Carbonic anhydrase inhibitors block reabsorption of what molecule?

NaHCO3

Carbonic anhydrase inhibitor examples?

Acetazolamide

Dichlorphenamide

Metazolamide

T/F: Carbonic anhydrase inhibitors have weak diuretic action.

True

T/F: Carbonic anhydrase inhibitors can contribute to hypokalemia.

True

T/F: Carbonic anhydrase inhibitors are sulfur-containing drugs.

True

Why do carbonic anhydrase inhibitors have the potential to increase urine pH?

Greater bicarbonate excretion -> increase in pH

What is the significance of increased pH in urine?

Increased H+ conc. in body, potential for acidosis

Clinical indications for carbonic anhydrase inhibitors? (three)

Glaucoma

Urinary alkalinization

Acute mountain sickness

MOA of acetazolamide?

Inhibits carbonic anhydrase, reduces exchange of Na+ for H+, resulting in mild diuresis

Side effects associated with acetazolamide?

Hypokalemia

Drowsiness

Paresthesia

Mild metabolic acidosis

T/F: Osmotic diuretics act in the thin descending limb of the loop of Henle.

True

T/F: The thin descending limb of the loop of Henle is highly permeable to water.

True

Osmotic diuretics remain in the lumen and ___________ water by virtue of their osmotic effect

A. Hold water

B. Release water

A. Hold water

What is the major location for osmotic agents' "water holding" action?

Proximal convoluted tubule

What is the function of Mannitol?

A. Inhibit the reabsorption of HCO 3-

B. Increase the reabsorption of HCO 3-

C. Increase the osmotic pressure in the kidney

D. Increase the reabsorption of Glucose

C. Increase the osmotic pressure in the kidney

Why is the thick ascending limb (TAL) called a diluting segment?

Because salt reabsorption in the TAL dilutes the tubular fluid

In the TAL, transporters mediating Na+/K+/Cl- reabsorption in the luminal membrane include? (two)

Na+/K+/2Cl- cotransporter (NKCC2)

K+ channel

In the TAL, transporters mediating Na+/K+/Cl- reabsorption in the basolateral membrane include? (two)

Na+/K+ ATPase

K+/Cl- porter

Loop diuretics are primarily concerned with what transporter?

NKCC2

Which class of diuretics is considered to be the most efficacious?

Loop diuretics

Loop Diuretics are considered to be potassium __________

A. Sparing

B. Wasting

B. Wasting

Loop diuretics are clinically applied where? (four)

1. Edema

2. Hypercalcemia

3. Hyperkalemia

4. Acute renal failure

Side effects associated with loop diuretics?

Hypokalemia

Ototoxicity

Hyperuricemia

Hypomagnesia

Acute hypovolemia

Hypotension, shock, arrhythmias

T/F: Loop diuretics have the potential to cause irreversible hearing loss.

True

Are loop diuretics appropriate in patients unable to urinate?

No; should not be used when patients are unable to urinate

Is it important for patients with kidney disease to inform their doctor prior to beginning a loop diuretic?

True

What is the duration of effect for furosemide?

2-3 hours

Oral absorption of furosemide takes about how long?

2-3 hours

T/F: Loop diuretics are eliminated by the kidney via glomerular filtration and tubular secretion.

True

What is the target of furosemide?

NKCC2

NCC

SGLT-2

Carbonic anhydrase

NKCC2

What is the function of furosemide?

Inhibit the reabsorption of HCO3-

Increase the reabsorption of HCO3-

Inhibit the reabsorption of Na+, K+, Cl-

Increase the reabsorption of Na+, K+, Cl-

Inhibit the reabsorption of Na+, K+, Cl-

Furosemide will _________ Ca2+ reabsorption

Increase

Inhibit

Not change

Inhibit

Furosemide is a _______ diuretic

A. Strong

B. Weak

A. Strong

Furosemide contains a __________ functional group

A. HCO3

B. Sulfonamide

C. Glucose

D. Zinc

B. Sulfonamide

Furosemide acts in the ________

A. PCT

B. Blood

C. Thick ascending limb of the loop of Henle

D. DCT

C. Thick ascending limb of the loop of Henle

Which one is not a loop diuretic?

A. Acetazolamide

B. Furosemide

C. Torsemide

D. Ethacrynic acid

A. Acetazolamide

Furosemide will __________ Mg2+ reabsorption

A. Increase

B. Inhibit

C. Not change

B. Inhibit

Thiazide examples? (three)

HCTZ

Indapamide

Metolazone

MOA of thiazide diuretics?

Inhibit Na+/Cl- cotransporter

Effects of thiazides in the DCT?

Reduce NaCl reabsorption -> diuresis

Enhance Ca2+ reabsorption

Thiazides are termed calcium _________ diuretics

A. Wasting

B. Sparing

B. Calcium-sparing diuretics

T/F: All thiazides have a sulfonamide group.

True

T/F: All thiazides can be administered orally.

True

Which thiazide has relatively low lipid solubility, warranting higher doses to achieve therapeutic effect?

Chlorothiazide

Therapeutic uses for thiazide diuretics? (four)

HTN

Edema

Hypercalcuria

Diabetes insipidus

Toxic effects of thiazide diuretics?

Hypokalemic metabolic alkalosis

Impaired carbohydrate tolerance

Hyperlipidemia

Hyponatremia

Impaired uric acid metabolism and gout

Allergic reactions (many sulfonamides)

Weakness, fatigability, paresthesias, etc.

What is the target of thiazide diuretics?

NCC

Which of the following is the mechanism of action of hydrochlorothiazide?

Inhibit the reabsorption of sodium and chloride in the distal convoluted tubule

Inhibit the reabsorption of sodium and chloride in the ascending loop of Henle

Inhibit the reabsorption of bicarbonate in the proximal convoluted tubule

Inhibit the reabsorption of bicarbonate in the collecting duct

A. Inhibit the reabsorption of sodium and chloride in the distal convoluted tubule

All thiazides are secreted in the ____________?

A. Proximal convoluted tubule

B. Blood

C. Thick ascending limb of Loop of Henle

D. Distal convoluted tubule

A. Proximal convoluted tubule

Thiazide diuretics act in the ____________

A. PCT

B. Blood

C. TAL of LoH

D. DCT

D. DCT

Ion transporter of interest in the collecting tubule systems?

ENaC

Na+ absorption in the collecting tubule system?

2-5% filtered

The collecting tubule system is the site of _____ secretion

potassium

Which channels in the luminal membrane of the collecting tubules are significant?

Na+ and K+ channels

Which channels in the basal membrane of the collecting tubules are significant?

Na+/K+ ATPase

Amiloride and triamterene block what transport channel?

Na+ channel blockers

Spironolactone and eplerenone mechanism of action?

Aldosterone antagonism

Side effects associated with K-sparing diuretics?

Hyperkalemia

Headache

Leg cramps

Spironolactone, eplerenone are __________ antagonists of aldosterone

A. Competitive

B. Non-competitive

A. Competitive

T/F: In the presence of ADH, the collecting tubule is impermeable to water.

False; in the absence of ADH, the collecting tubule is impermeable to water.

Role of ADH?

Increases permeability, leading to more concentrated urine

ADH antagonist examples?

Conivaptan, tolvaptan

Conivaptan is an ADH inhibitor at what receptors?

V1a, V2

Tolvaptan is an ADH inhibitor at what receptors?

More selective V2 blocker with little V1 affinity

What is the target of amiloride?

A. NKCC2

B. NCC

C. ENaC

D. Carbonic anhydrase

C. ENaC

Why use loop agents + thiazides?

Synergistic effects to overcome drug refractory by reducing compensatory effects to a single drug

Why potassium-sparing diuretics + other diuretics?

Balance the effects of diuretics on K+ flux

Which two diuretic types can decrease body pH?

Carbonic anhydrase inhibitors

K+ sparing agents

Which two diuretics have the greatest effect on NaCl excretion?

Loop agents first

Thiazides second