Diuretics- Prof K

What are the main functions of the kidney?

• regulate ECF vol

• regulate osmotic pressure thru urine excretion

• regulate conc of electrolytes

• regulate bp

• eliminate waste

• remove drugs/foreign components

• filters around 180L of blood a day

What are the board indications for diuretics?

• Edema

• Hypertension

• CHF

• Prevent renal damage

General actions of diuretics:

1. increase urine output

2. increase/decrease electrolyte excretion

3 thiazide diuretics to know:

1. hydrochlorothiazide

2. chlorothiazide

3. chlorthalidone

Do thiazides have a small, moderate, or severe diuretic action?

moderate

What part of the nephron do thiazides effect?

distal tubule

A thiazide diuretic has what 3 main structural components?

1. benzo ring

2. dioxide

3. thiadiazine

How does the structure of Chlorothiazide/Hydrochlorothiazide differ from chlorthalidone?

No thiadiazine ring in chlorthalidone

What group is absolutely necessary in the structure for thiazide function?

sulfonamide

An electron-_________ group on position 6 would decrease reactivity.

donating

An electron-donating group like a -Cl group on position ____ would increase reactivity of a thiazide.

6

On position 2 of a thiazide diuretic, what increases the duration of action?

alkyl substitution

• Ex: methyl, ethyl, propyl (a carbon chain)

On position 3 of a thiazide diuretic, what would increase potency and duration of action?

hydrophobic group

• Ex: methyl, benzene ring, haloalkyl

Does saturation of the 3-4 bond of a thiazide increase or decrease potency?

increase

Which is more potent, Hydrochlorothiazide or Chlorothiazide?

Hydrochlorothiazide

MOA of thiazide diuretics

inhibits Na/Cl symporter in distal tubule

Indications of Thiazides

• Edema

• Hypertension

• Heart Failure

• Nephrolithiasis due to excess Ca

• Nephrogenic Diabetes Insipidus

What are the Acute Antihypertensive effects of thiazide diuretics?

• increase Na excretion

• decrease intravascular vol, cardiac output, and BP

What are the chronic antihypertensive effects of thiazide diuretics?

• vol and cardiac output returns to normal

• BP stays decreased

• decrease vascular resistance

What are the ADRs on electrolytes for thiazide diuretics?

HYPO

• hypomagnesemia

• hyponatremia

• hypokalemia

HYPER

• hypercalcemia

What are the metabolic changes seen with thiazides diuretics?

Think: Hyper everything

• hyperuricemia

• hyperglycemia

• hyperlipidemia

What group on the structure of the thiazide diuretics has the potential to cause hypersensitivity reactions? (Hives, swelling, N/V, HA, etc.)

sulfonamide

Thiazides are contraindicated in anyone with…

sulfonamide allergy.

What drugs interact with thiazides in an additive/synergistic way?

• Loop diuretics

• Antihypertensive drugs

What drugs interact with loop diuretics in an additive/synergistic way?

• thiazide diuretics

• Antihypertensive drugs

What drugs interact with thiazides in a way that we want to watch/avoid the drug altogether?

• lithium

  • seizures, shakes

• NSAIDs

  • makes thiazides not work

• Dofetilide

  • severe arrythmias

What drugs interact with loop diuretics in a way that we want to watch/avoid the drug altogether?

• lithium

• NSAIDs

• Digoxin

  • arrythmias

• Aminoglycosides

  • may induce hearing loss

Names of the 4 loop diuretics to know:

1. furosemide

2. torsemide

3. bumetanide

4. ethacrynic acid

Site of Action of loop diuretics:

ascending limb of loop of henle

How does the structures of the other loop diuretics differ from Ethacrynic acid?

Ethacrynic acid has no sulfoamide

Loop Diuretics block what transporter?

NKCC

How does Loop diuretics effect magnesium, calcium, and potassium?

Think: HYPOOOOOOO

• hypokalemic metabolic alkalosis

• hypomagnesemia

• hypocalcemia

Loop Diuretics and Thiazide diuretics all have similar effects on electrolytes and metabolic changes EXCEPT FOR:

calcium

loop- hypocalcemia

thiazides- hypercalcemia

Why does hypokalemia caused by loop diuretics cause metabolic alkalosis?

bc increased excretion of K and H causes a bicarb buildup. Bicarbonate is a base, so a lot of base= alkalosis

Can ototoxicity caused by diuretics be reversed?

yes- usually

Loop Diuretics are contraindicated in pts with:

• Sulfonamide allergy

  • except ethacrynic acid

• severe Na or volume depletion

  • pretty obvious

• anuria

Indications of Loop Diuretics:

• Edema

  • pulmonary, hepatic, cardiac, renal

• hypertension

• acute renal failure

• hyperkalemia

• hypercalcemia

What diuretic has the possibility of causing hearing issues? (otoxicity)

loop diuretics

4 Potassium sparing diuretics to know:

1. spironolactone

2. eplerenone

3. triamterene

4. amiloride

What are the 2 MOAs for Potassium sparing diuretics?

1. Inhibit ENac

2. Inhibit Aldosterone

Site of action of potassium sparing diuretics:

cortical collecting duct

• (principal cells)

Which Potassium sparing diuretics act as aldosterone antagonists?

1. Spironolactone

2. Eplerenone

Which potassium sparing diuretics act as ENac inhibitors?

1. Triamterene

2. Amiloride

If Aldosterone works to increase sodium resorption and increase potassium excretion, Aldosterone Antagonists do what?

• decrease sodium resorption

• decrease potassium excretion

How do Potssium sparing diuretics that are Aldosterone Antagonists inhibit aldosterone? (MOA)

• competitively bind to the receptor where aldosterone would bind (mineral corticoid receptor)

• causes less ENac and Na/K pumps to work

• end result: less Na reabsorbed and less K excreted

Which Potassium Sparing diuretic is a prodrug?

What is the active metabolite of this diuretic called?

How does the structures of these 2 differ?

• Spironolactone

• Active metabolite- Canrenone

• Structurally- Spironolactone has a thio-acetyl, canernone doesn’t

ADRs of Potassium Sparing Diuretics that are Aldosterone Antagonists:

• hyperkalemia

• metabolic acidosis

• endocrine effects (only spironolactone)

Which diuretic has the potential to cause gynecomastia, an endocrine problem?

spironolactone

Which diuretic would I chose if I didn’t want the potential endocrine side effects that spironolactone has?

eplerenone

Indications of Potssium Sparing Diuretics:

• Aldosterone Antagonists

• ENac Inhibitors

BOTH:

• CHF

• Hypertension

• Hypokalemia

JUST Aldosterone Antagonists:

• Edema

• Primary Aldosteronism

• Femal Hirsutism

  • only spironolactone

Contraindications of Aldosterone Antagonists:

• K supplements

• other K sparing diuretics

• Hyperkalemia

• decreased renal function

Recognize the components of Potassium Sparing Diuretics that are ENac inhibitors:

• pyrimidine

• pyrazine

• pterdine ring

Common ADRs of Potassium Sparing Diuretics that are ENac Inhibitors:

• Hyperkalemia

• Metabolic Acidosis

• N/V, HA

Name of an osmotic diuretic:

mannitol

Site of action of osmotic diuretics:

• proximal tubule

• descending limb of loop of henle

Mannitol has no other effects other than attracting _______.

water

Mannitol is classified as what?

sugar alcohol

How does mannitol attract water out of the cells?

• it’s structure- it has a bunch of alcohol groups and that attracts water

ADRs of osmotic diuretics:

• hyperkalemia

• hypernatremia

• N/V, HA

Contraindications of osmotic diuretics:

• anuria

• dehydration

Indication of osmotic diuretics:

• acute renal failure

• reduces intracranial or intraocular pressures

What is the name of the carbonic anhydrase inhibitor we have to know?

Acetazolamide

Acetazolamide inhibits reabsorption of what 2 things?

• Na

• Bicarbonate

Acetazolamide acts on what part of the nephron?

proximal tubule

ADRs of Carbonic Anhydrase Inhibitors

• Metabolic acidosis

• hypokalemia

• vomiting

Indications of Carbonic Anhydrase Inhibitors:

• glaucoma

• metabolic alkalosis

• moutain sickness