Medicinal Chemistry of Diuretic Agents

acetazolamide

a-suh-tuh-zow-luh-mide

(Diamox)

spironolactone

(Aldactone)

Diuretic def-

a substance that increases the rate of urine formation (typically via natriuretic-excretion of an abnormally large amount of sodium and water effects)

Electrolyte def-

a substance that becomes an ion in solution (e.g. sodium (Na+))

Hypokalemia def-

an abnormally low (<3.5 mEq/L) concentration of potassium (K+) in the blood; primary symptoms are muscle weakness and polyuria

Hyponatremia def-

an abnormally low (<136 mEq/L) concentration of sodium (Na+) in the blood; primary symptom is CNS dysfunction (confusion, nausea, seizures, etc.)

Mineralocorticoid def-

a type of hormone (e.g. aldosterone) that regulates the balance of water & electrolytes in the body (cf. to glucocorticoids & sex steroids)

Natriuretic def-

a substance that increases the rate & amount of sodium (Na+) elimination in the urine

Drug classes that are used for Edema and Hypertension-

Loops, Thiazides, K+-sparing

Carbonic anhydrase inhibitors

Site of action: proximal (convoluted) tubule

Mechanism of action: inhibition of carbonic anhydrase

CC- arylsulfonamide

acetaZOLAMIDE (Diamox)

MOA-

CC-

MOA- inhibition of carbonic anhydrase

CC- arylsulfonamide

Carbonic anhydrase inhibitors SAR-

(acidic) arylsulfonamide group required for interaction with the catalytic zinc atom in the active site of human carbonic anhydrase

Loop Diuretics

Site of action: ascending limb of loop of Henle (most efficacious site of action)

Mechanism of action (MOA): inhibition of the Na+/K+/2Cl- (NKCC2) cotransporter 2 (or symporter) & Na+,K+-ATPase

CC: arylsulfonamide

ethacrynic acid & ethyacrynate sodium (Edecrin)

Does not have sulfonamide. Used for Sufa allergies.

furosemide (Lasix)

furosemide (Lasix) formulations

Furoscix (SQ furosemide)

Enbumyst (IN bumetanide)

Thiazides & Derivatives

Site of action: distal (convoluted) tubule (site 3)

Mechanism of action (MOA/PC): inhibition of the Na+/Cl- cotransporter (or symporter, NCC) (also inhibition of carbonic anhydrase at higher doses)

Thiazides & Derivatives SAR-

hydrochlorothiazide (HCTZ, HydroDiuril)

Thiazides & Derivatives ADR’s-

potential for volume and electrolyte disturbances (hyponatremia, hypokalemia), hyperuricemia (high level of uric acid in the blood)

Potassium-sparing agents

Site of action: the principal & intercalated cells of the connecting & cortical collecting tubule

Mechanism of action (MOA):

Aldosterone receptor antagonism (the “renones”or MRAs): spironolactone (Aldactone), eplerenone (Inspra), finerenone [(Kerendia) (does not have a Steriod SAR)]

Blockade of epithelial sodium (Na+) channels (ENaC) in the principal cells: aMILoride (as the HCl salt in Midamor) and triamterene (Dyrenium)

CC: progesterone derivatives OR diaminopyrimidine derivatives

Potassium-Sparing Agents ADR’s-

hyperkalemia, which can be fatal

sexual side effects (blocking testosterone receptors and lowering androgen activity)

Orthostatic Hypotension

Other diuretic agents

Osmotics

Xanthines

Vaptans

Thiazides & Derivatives

MOA: Na+/Cl- cotransporter (NCC) inhibitors

(also inhibition of carbonic anhydrase at higher doses)

CC: thiazides & derivatives

chlorthalidone (Hygroton)

spironolactone (Aldactone)

triamterene (Dyrenium/ Maxzide)

sodium Channel (ENaC) blockers

Loop Diuretics ADR’s-

profound diuresis (Urine production) & electrolyte depletion

Carbonic anhydrase inhibitors ADR’s-

parasthesias, GI distress, taste alterations, CNS effects (e.g. drowsiness, confusion), polyuria, and hearing disturbances

Red Flags- Severe Cutaneous Adverse Reactions (SCARs)=SJS/TEN, severe abnormality or disease of the blood, kidney stones, hepatic toxicity