Medicinal Chemistry of Renal Medications (33)

Mannitol (Osmotic Diuretic)

Acetazolamide (CAI)

Methazolamide (CAI)

Dorzolamide (CAI)

Brinzolamide (CAI)

Hydrochlorothiazide (Thiazide Diuretic)

Metolazone (Thiazide-like Diuretic)

Ethacrynic Acid (Loop Diuretic)

Furosemide (Loop Diuretic)

Bumetanide (Loop Diuretics)

Torsemide (Loop Diuretic)

Aldosterone (Aldosterone Antagonists)

Spironolactone (Aldosterone Antagonists)

Eplerenone (Aldosterone Antagonist)

Triamterene (K+ Sparing)

Amiloride (K+ Sparing)

What is the MOA of Osmotic Diuretics?

Low MW compounds, filtered through Bowman’s capsule into the renal tubules (Non-reabsorbable)

Work indirectly by increasing the filtrate osmolarity & preventing water loss from luminal fluid by osmosis

What is the site of action for Osmotic Diuretics?

Proximal tubule

Loop of Henle

Collecting Duct

What is the potency of Osmotic Diuretics?

Weak Diuretics

What is an example of Osmotic Diuretics?

Mannitol

What is the MOA of Carbonic Anhydrase Inhibitors?

Prevents sodium reuptake by inhibiting carbonic anhydrase which provides H+ intracellularly to drive the Na+/H+ transporter

What is the site of action of Carbonic Anhydrase Inhibitors?

Proximal & Distal tubular cells

most effect seen from PCT

What is the potency of Carbonic Anhydrase Inhibitors?

Weak due to offset by increased action of sodium reupsorption at loop of Henle

What is an example of Carbonic Anhydrase Inhibitors?

Acetazolamide

What is the MOA of Thiazide Diuretics?

Inhibition of chloride binding to Na+/Cl- reabsorption

What is the site of action of Thiazide Diuretics?

Proximal tubule

Major: Distal tubule

What is the potency of Thiazide Diuretics?

High degree of diuretic action

What is an example of a Thiazide Diuretic?

Hydrochlorothiazide

What is the MOA of Thiazide-like diuretics?

inhibit Na+/Cl- symporter (NCC)

What is the site of action for Thiazide-like diuretics?

Distal convoluted tubule

What is the potency of Thiazide-like diuretics?

Weak diuretics

What is an example of thiazide-like diuretics?

Chlorthalidone

What are Indolines?

Differ from thiazides by absence of thiazide ring & only one sulfonamide group

What is the DOA of Indolines?

up to 8 weeks

What is an example of Indoline?

Indapamide (Lozol)

What is the MOA of Loop Diuretics?

Inhibition of luminal sodium potassium chloride symporter (Na+/K+2cl-)

Directly affect water reabsorption from descending limb

What is the site of action of Loop Diuretics?

Thick ascending limb of Loop of Henle

What is the potency of Loop Diuretics?

Most potent class of Diuretics

Loop Diuretics are characterized by quick onsets of action and short durations of action

What is Ethacrynic Acid?

Phenoxyacetic acid derivative

Safe for use in patients with sulfonamide allergies

What are the loop diuretic drugs?

Furosemide

Bumetanide

Torsemide

Ethacrynic acid

What is the MOA of Aldosterone Antagonists?

Aldosterone antagonists bind to & inhibit this receptor, preventing up-regulation of the Na+/K+ pumps

What is the Site of Action of Aldosterone Antagonists?

Late distal tubule & collecting duct

What is the potency of Aldosterone Antagonists?

Weak Diuretics

What are examples of Aldosterone Antagonists?

Spironolactone

Eplerenone

What is the MOA of K+ Sparing Diuretics?

Blockage of epithelial sodium channels (ENaC) (sodium-potassium channel)

Block reabsorption of sodium & inhibit secretion of potassium ions

What is the site of action for K+ sparing diuretics?

Principal cells in the late distal tubules & collecting ducts

What is the potency of K+ Sparing Diuretics?

Weak

What is the indications of K+ Sparing Diuretics?

Rarely used solely; most often in combo with thiazide diuretics to offset hypokalemia

What is an example of potassium sparing diuretics?

Triamterene

Amiloride

What are the adverse effects of Osmotic Diuretics?

Alteration of blood sodium levels

What are the therapeutic applications of Osmotic Diuretics?

Prophylaxis of acute renal failure; reduction of intracranial pressure or intraocular pressure

What can Osmotic Diuretics do and not be used to treat?

increase extracellular fluid

should not be used to treat edema or CHF

What are the adverse effects of Carbonic Anhydrase Inhibitors?

Minor electrolyte disturbances

GI, CNS, kidney stones

Prolonged use can lead to metabolic acidosis

What are the therapeutic applications of Carbonic Anhydrase Inhibitors?

Limited use due to loss of potency as acidosis develops with use

Glaucoma

What are the adverse effects of Thiazide Diuretics?

Hypersensitivity

GI upset

Electrolyte imbalances

Hypokalemia

What are the therapeutic application for thiazide diuretics?

Edema caused by CHF, hepatic, or renal disease

Commonly used for treatment of HTN

What are the adverse effects of Loop Diuretics?

Hypokalemia

Hyperuricemia

What are the Adverse effects of Aldosterone Antagonists?

Hyperkalemia

Hypersensitivity

GI efftects

peptic ulcer

Sexual side effect: Gynomastia, decreased libido (Spironolactone)

What are the indications for the usage of Eplerenone?

HTN

Left ventricular dysfunction

CHF after MI

What are the adverse effects of Triamterene?

Hyperkalemia

N/V

Headache

What are the indications for use of Triamterene?

HTN

Edema

What is the SAR of Osmotic Diuretics?

Many OH groups, highly polar

not metabolized

not reabsorbed

What is the SAR of CAI?

Suflonamide groups

Lipophilicity influences tissue distribution

What is the SAR of Thiazides?

E withdrawing & donating increases & decreases activity

Saturation of 3,4-double bond (HCTZ) increases potency

What is the SAR of Thiazide-like diuretics?

E withdrawing & donating increases and decreases activity

What is the SAR of Loop Diuretics?

Electron-withdrawing group at aromatic ring enhances potency

High protein binding

What is the SAR of Aldosterone Antagonists?

Steroid nucleus mimics aldosterone

Eplerenone: expoxy group → increases selectivity and decreases endocrine side effects

What is the SAR of Potassium Sparing Diuretics?

Amiloride: Guanidinium group = essential for cationic binding at ENaC

Triamterene: Pteridine ring with amino groups required

What ist he transport mechanism to SOA of Osmotic Diuretics?

Freely filtered at glomerulus

Not reabsorbed and not metabolized → remain in tubular lumen

Transport mechanism of Carbonic Anhydrase Inhibitors to SOA?

secreted in proximal tubule by organic anion transporters (OATs)

What is the transport mechanism of Thiazides to SOA?

Secreted in proximal tubules by OATs

What is the transport mechanism of thiazide-like diuretics to SOA?

same as thiazides

What is the Transport mechanism of Loop Diuretics to SOA?

Protein-bound not filtered at glomerulus

delivered to lumen via OATs in proximal tubule

What is the transport mechanism of Aldosterone Antagonists to SOA?

Lipophilic steroid analogs → passively diffuse across cell membranes

What is the transport mechanism of Potassium Sparing Diuretics to SOA?

secreted in lumen by organic cation transporter (OCTS) in proximal tubule