Diuretic Pharmacology – Structural Features, Potency, and Mechanisms

Sixty question-and-answer flashcards covering the structural pharmacology, potency determinants, mechanisms of action, and classification of sulfonamide-based, loop, thiazide, and potassium-sparing diuretics.

What two structural elements form the basic pharmacophore of a sulfonamide-type diuretic?

(1) An unsubstituted sulfonamide group (-SO₂NH₂) and (2) an ortho electron-withdrawing group on the aromatic ring.

Which functional group is essential for the activity of thiazide and loop diuretics?

The unsubstituted sulfonamide (-SO₂NH₂) group.

Give two common electron-withdrawing groups (EWGs) used next to the sulfonamide in thiazide diuretics.

Chlorine (Cl) and trifluoromethyl (CF₃).

Why is an electron-withdrawing group required in the sulfonamide diuretic pharmacophore?

It increases diuretic activity by enhancing binding to the renal target.

Saturating the double bond in the thiazide ring system has what effect on potency?

It increases potency about 10-fold.

What effect does adding a lipophilic group at the C3 position have on a thiazide diuretic?

It increases potency and lengthens duration of action.

Which thiazide diuretic is predicted to be the most potent based on structure?

Polythiazide.

Why is Polythiazide predicted to show the highest potency among thiazides?

It has both a saturated ring and a highly lipophilic substituent at C3.

Which thiazide diuretic is predicted to have the longest duration of action?

Polythiazide.

Why does Polythiazide have the longest duration of action?

Its very lipophilic C3 substituent slows renal elimination.

What role does a chlorine atom play when attached to a thiazide diuretic?

The chlorine acts as an electron-withdrawing group that enhances diuretic activity.

Which thiazide diuretic can be administered intravenously?

Chlorothiazide.

Why is Chlorothiazide suitable for parenteral (IV) administration?

Its acidic sulfonamide proton (pKa ≈ 6.7) allows formation of a water-soluble sodium salt.

What is the approximate pKa of the acidic proton in Chlorothiazide that permits salt formation?

About 6.7.

Why can most “hydro-” thiazides not be converted to water-soluble salts for IV use?

They lack the double bond that makes the sulfonamide proton acidic enough for salt formation.

Loop diuretics inhibit which specific transporter?

The Na⁺/K⁺/2Cl⁻ symporter.

In which segment of the nephron do loop diuretics act?

The thick ascending limb of the Loop of Henle.

Relative to other diuretic classes, how efficacious are loop diuretics?

They are the most efficacious (most powerful) diuretic class.

List the two main ways potassium-sparing diuretics conserve potassium.

(1) Aldosterone receptor antagonism and (2) direct ENaC (epithelial sodium channel) blockade.

How does spironolactone act as a potassium-sparing diuretic?

It antagonizes aldosterone receptors, preventing synthesis of ENaC proteins.

Which potassium-sparing diuretic directly blocks ENaC?

Amiloride (also Triamterene).

Name two ENaC-blocking potassium-sparing diuretics.

Amiloride and Triamterene.

What are the three main structural classes of diuretics?

(1) Thiazide and thiazide-like, (2) loop, and (3) potassium-sparing diuretics.

What core structure defines thiazide diuretics?

A benzothiadiazine-1,1-dioxide ring containing the sulfonamide pharmacophore.

Most loop diuretics (except Ethacrynic acid) are based on what chemical scaffold?

An anthranilic acid scaffold that includes a sulfonamide group.

Which loop diuretic lacks a sulfonamide group?

Ethacrynic acid.

Why might Ethacrynic acid be selected for a sulfonamide-allergic patient?

Because it lacks the sulfonamide group responsible for allergy risk.

Name a steroid-derived potassium-sparing diuretic.

Spironolactone.

Which potassium-sparing diuretic has a pteridine-based structure?

Triamterene (also amiloride).

Where in the nephron do potassium-sparing diuretics exert their main effect?

In the collecting ducts.

Blocking ENaC has what effect on potassium excretion?

It decreases potassium excretion (spares potassium).

At which carbon position does Polythiazide carry its large lipophilic substituent?

The C3 position of the thiazide ring.

Saturation of which bond in thiazide diuretics boosts potency?

The ring double bond adjacent to the sulfonamide group.

By approximately how many fold does double-bond saturation increase thiazide potency?

About ten-fold.

Which sulfonamide group must remain unsubstituted for diuretic activity?

The ‑SO₂NH₂ moiety.

Which class of diuretics produces the greatest sodium and water excretion?

Loop diuretics.

What happens to ENaC protein production when aldosterone receptors are blocked?

Production of ENaC proteins is prevented, reducing sodium reabsorption.

What does ENaC stand for?

Epithelial Sodium Channel.

Provide the chemical abbreviation for the trifluoromethyl electron-withdrawing group.

CF₃.

Give one common halogen used as an electron-withdrawing substituent in diuretics.

Chlorine (Cl).

Which structural class of diuretics contains the benzothiadiazine-1,1-dioxide core?

Thiazide and thiazide-like diuretics.

How is the anthranilic acid scaffold relevant to loop diuretics?

Most sulfonamide loop diuretics are built on an anthranilic acid framework.

True or False: Ethacrynic acid contains a sulfonamide group.

False.

What is the main purpose of the electron-withdrawing group in a diuretic pharmacophore?

To enhance binding and thereby increase diuretic activity.

What property must a diuretic possess to be formulated for intravenous injection?

Adequate water solubility (often achieved via salt formation).

Chlorothiazide becomes water soluble for IV use when converted to what salt?

Its sodium salt.

In aromatic chemistry, what does the term “ortho” refer to?

A substituent located adjacent to another on the aromatic ring (1,2-relationship).

Adding a lipophilic group at C3 primarily increases which pharmacokinetic property of thiazides?

Duration of action (by increasing tissue binding and decreasing clearance).

Which proton in Chlorothiazide is acidic enough to allow salt formation?

The proton on one of its sulfonamide groups.

Which is both the most potent and longest-acting thiazide among those discussed?

Polythiazide.

Does a lipophilic C3 group increase thiazide duration, potency, or both?

Both potency and duration.

Electron-donating groups ortho to the sulfonamide will have what effect on activity?

They decrease diuretic activity.

What general effect does adding lipophilicity have on a drug’s renal clearance?

It usually decreases renal clearance, prolonging action.

Blocking the Na⁺/K⁺/2Cl⁻ symporter prevents reabsorption of which primary ion?

Sodium (Na⁺), along with K⁺ and 2Cl⁻.

What hormone’s receptor is antagonized by spironolactone?

Aldosterone.

Why do ENaC blockers spare potassium?

Because preventing sodium entry reduces the driving force for potassium secretion.

Which structural change distinguishes Chlorothiazide from Hydrochlorothiazide regarding IV use?

Chlorothiazide retains an acidic proton due to a double bond absent in Hydrochlorothiazide.

What is the principal pharmacological advantage of loop diuretics over thiazides?

Greater diuretic efficacy, especially in high-sodium states.

Identify a pteridine-based ENaC blocker used clinically.

Amiloride.

Which part of the Loop of Henle do loop diuretics target?

The thick ascending limb.

What structural feature must remain unsubstituted on sulfonamide diuretics for activity?

The nitrogen of the sulfonamide (-SO₂NH₂) must be unsubstituted.