Diuretics and Hypertension

• The presentation is about antihypertensives, specifically diuretics, in Pharmacology & Medicinal Chemistry PHRM 6104, for Spring 2025, presented by Kathleen Frey, Ph.D.
• Office hours are on Monday and Wednesday from 10-11:30am by appointment.
• The email address is [email protected].

Lecture Objectives

• General actions/MOA of diuretics.
• Distinguishing diuretic classes based on pharmacophore or structure activity relationships (SAR).
• Specific mechanism of action, pharmacodynamics, site of action, therapeutic effect, and adverse effects for all diuretic classes.
• Identifying acidic or basic groups (in diuretics) that enhance binding to ion transporters in the kidney.
• Recognizing the structure of mineralocorticoid receptor (MR) antagonists and how their structure relates to steroidal hormones.
• How drug physiochemical properties impact efficacy, metabolism, and toxicity.

Lecture Outline

• Review of hypertension therapeutic strategies.
• An overview of diuretics.
• Pharmacology and medicinal chemistry: classes, specific drugs, mechanism of action, SAR/Med Chem, physiochemical properties & PK, adverse effects, and clinical applications.

Basic Pharmacology Model: Hypertension

• Hypertension is a disease state associated with sustained, and abnormally high blood pressure.
• Normal: physiology includes normal blood pressure, regulated blood volume, and kidney function.
• Hypertension: pathophysiology includes increased blood volume and SVR.
• Treatment uses diuretics to decrease blood volume and SVR.

Renal Physiology: Function

• Kidneys filter blood plasma and produce urine for bodily excretion of metabolic waste products.
• Kidneys reabsorb glucose, amino acids, and ions.
• Glomerular filtration filters plasma through specialized capillaries into the renal tubules.
• Renal tubules remove water, solutes from the filtered fluid or secrete solutes into the fluid.
• Specialized ion transporters remove/secrete solutes/water.
• Abnormally elevated total body salt/water retention leads to an increased blood volume.

Anatomy of the Kidney

• Nephron: is the functional unit of the kidney.
• Glomerulus: filters blood.
• Proximal Tubule: reabsorbs Na+.
• Loop of Henle: diuretics start to work here.
• Distal Convoluted Tubule (DCT): thiazides work here.
• Collecting Duct (CD; or tubule): potassium-sparing diuretics act here.

Renal Physiology: Key Kidney Ion Transporters

• Proximal Tubule Cell: promotes excretion with Na reabsorption.
• Distal Convoluted Tubule Cell: includes a Na/Cl cotransporter to excrete Na+.
• Thick Ascending Limb Cell: the Na transporter controls ions from getting into the Loop of Henle; if blocked, they get excreted.
• Collecting Duct Principal Cell: is an epithelial Na channel that excretes Na+.

Review of Renal Physiology & Function

• Glomerulus: forms glomerular filtrate (no major diuretic action).
• Proximal Convoluted Tubule (PCT): reabsorbs 65% of filtered Na+/K+/Ca2+/Mg2+, 85% of NaHCO3, and nearly 100% of glucose with an isosmotic reabsorption of water.
  • The Primary Transporters/Drug Targets include Na/H¹ (NHE3), carbonic anhydrase, and Na/glucose cotransporter 2 (SGLT2).
  • Carbonic anhydrase inhibitors and adenosine antagonists (under investigation) inhibit this tubule's reabsorption.
• Proximal tubule, straight segments: reabsorbs & secretes organic acids/bases, uric acid, and diuretics.
  • Acid (eg, uric acid) and base transporters are the Primary Transporters/Drug Targets
  • None diuretics inhibit this tubule's reabsorption.
• Thin descending limb of Henle's loop: passively reabsorbs water.
  • Aquaporins are the Primary Transporters/Drug Targets, no major diuretic action.
• Thick ascending limb of Henle's loop (TAL): actively reabsorbs 15-25% of filtered Na+/K+/Cl; and secondarily reabsorbs CA2+/Mg2+.
  • Na/K/2Cl (NKCC2) is the Primary Transporters/Drug Target; loop diuretics inhibit this tubule's reabsorption.
• Distal convoluted tubule (DCT): actively reabsorbs 4-8% of filtered Na+/Cl-; and CA2 reabsorbed under parathyroid hormone control.
  • Na/Cl (NCC) is the Primary Transporters/Drug Target; thiazides inhibit this tubule's reabsorption.
• Cortical collecting tubule (CCT): Na reabsorption (2-5%) relates to K/H secretion.
  • Primary Transporters/Drug Targets include Na channels (ENaC), K channels, H transporters, and aquaporins.
  • K+-sparing diuretics and Adenosine antagonists (investigation) inhibits this tubule's reabsorption.
• Medullary collecting duct: reabsorbs water under vasopressin control; vasopressin antagonists inhibit this tubule's reabsorption.
  • Aquaporins are the Primary Transporters/Drug Target.

Renal Physiology: Kidney & Blood Volume Control

• The cycle contains venous blood storage, pump output from the heart, arteriolar resistance, CNS sympathetic nerves communication, and kidney volume.

Pathophysiology: Hypertension

• Formula is↑BP = ↑CO x ↑SVR
• Increased CO: caused by abnormal sympathetic activation.
• Increased SVR: caused by blood vessel vasoconstriction (sympathetic control or vasoactive substances), increased blood volume (Failure of RAAS; Na+/water retention).

Review Pathophysiology: Hypertension

• In primary hypertension, impaired regulatory mechanisms now sustain high blood pressure.
• Malfunctions: abnormal neuronal mechanisms (sympathetic/ANS), failure of RAAS to control blood volume/pressure, defects in peripheral regulation (ANS/baroreceptors), disturbances in calcium, sodium, or natriuretic hormones.
• Many factors are due to malfunction in RAAS (long term control), or may result from several concurrent malfunctions.

Basic Pharmacology Model: Hypertension

• Hypertension is a disease state associated with sustained, abnormally high blood pressure.
• Normal: physiology includes normal blood pressure, regulated blood volume, and kidney function.
• Hypertension: pathophysiology is increased blood volume and PVR.
• Fixed: treatment strategies with pharmacological therapy and diuretics (decreased Na+ & H2O loss).

Hypertension: Therapeutic Approaches

• Decrease sympathetic outflow or cause vasodilation (Beta blockers; a₂ agonists).
• Prevent Na+ reabsorption/Promote Na+ Excretion (Diuretics).
• Inhibit Renin-Angiotensin-Aldosterone System (RAAS)
  • Block the production of Angiotensin II (ACE inhibitors)
  • Block the action of Angiotensin Receptors (Angiotensin II Receptor Blocker, ARBs)
  • Block Renin from producing Angiotensin I (Renin Inhibitor)
• Promote Vasodilation (Vasodilators; α₁ antagonists)
• Block voltage gated calcium channels to decrease cardiac output and/or cause vasodilation (Calcium Channel Blockers, CCBs)

General MOA of Diuretics

• General action: directly decrease blood volume by reducing salt reabsorption/water retention in the kidney.
• Increase the rate of urine production and electrolyte excretion (Na+ and Cl- ions), and water (without affecting other blood components).
• Agents prevent Na+ reabsorption or promote diuresis (water loss).
• May also induce renal prostaglandin synthesis, contributing to increased blood flow in the kidney (thiazides/loop diuretics rely on prostaglandins).
• Therapeutic uses: hypertension, congestive heart failure, and pulmonary edema (gets rid of fluid in lungs).

Diuretics: Classes, Sites of Action, and MOA

• Proximal tubule diuretics: Acetazolamide.
• Loop of Henle diuretics: Mannitol, Loop diuretics, Aldosterone antagonists (MRA)
• Distal convoluted tubule (DCT): Thiazide diuretics.

Diuretics: Classes, Sites and Mechanisms of Action

• Osmotics: proximal tubule & Loop of Henle.
• Carbonic anhydrase inhibitors: proximal convoluted tubule.
• Thiazides and thiazide like: cortical portion of the thick ascending limb of loop of Henle and the distal tubule.
• Loop or high-ceiling: Thick ascending limb of the loop of Henle.
• Potassium-sparing: Distal tubule and collecting duct.
• Most diuretics directly act on ion transporters in the kidney.

Diuretics Used for Hypertension

• Loop (High Ceiling) Diuretics.
• Thiazides & Thiazide-like Diuretics.
• Potassium Sparing Diuretics
  • Potassium Sparing Diuretics (non-MR Antagonists)
  • Mineralocorticoid Receptor (MR) Antagonists

Loop (High Ceiling) Diuretics

• Loop diuretics inhibit the luminal Na+/K+/2Cl- transporter (NKCC2) in the thick ascending limb of the Loop of Henle.
• Reduce the reabsorption NaCl, or K+ positive potential.
• Decreased positive potential causes significant Mg2+ and Ca2+ loss.
• High ceiling diuretics produce greater diuresis than other classes.
• Used for acute pulmonary edema, heart failure and sometimes for hypertension.
• Specific Drugs: Furosemide (Lasix)*, Torsemide, Bumetanide, or Ethacrynic acid.

Loop Diuretics: MOA & Pharmacodynamics

• The diuretics inhibit a Na+/K+/2Cl- transporter (NKCC2) located inside the lumen in the thick ascending Limb Cell, reduce NaCl reabsorption, and the lumen's positive potential.
• Reduced lumen potential causes increased Magnesium and Calcium excretion which will require a positive potential, which may cause hypomagnesemia for some patients (due to the adverse effect).

Loop Diuretic: SAR for Benzoic Acids

• Furosemide and bumetanide are benzoic acid loop diuretics; these structures include benzoic acid (scaffold) with attached unsubstituted sulfonamide group (Red).
• Sulfonamide functional group (acidic group) interacts with positively charged regions (basic amino acids) of NKCC2.
• Electronegative groups, such as Cl and phenoxy oxygen, withdraw electrons, making the para carboxylic acid more acidic (COOH pKa ~ 3.9).

Loop Diuretics: SAR for Non-Benzoic Acids

• Includes torsemide and ethacrynic acid,
• Torsemide retains the sulfonamide group (substituted).
• Ethacrynic acid does not have the sulfonamide group, but it does feature an acidic carboxylic acid group.

Loop Diuretics: Physiochemical Properties & PK

• The diuretics are limited as a first-line anti-hypertensive.
• Has a fast onset, a short half-life, and an overall short duration of action (~6 hours); limits their use as antihypertensives.
• Drugs excrete primarily in urine
• Torsemide is prone to CYP2C9 oxidation of the methyl tolyl group to a carboxylic acid (producing an inactive metabolite).

Loop Diuretics: Toxicity & Adverse Effects

• Associated with electrolyte imbalances by hypomagnesemia, hypocalcemia, and hypercalciuria due to increased Mg2+ and Ca2+ excretion.
• Hypokalemic metabolic alkalosis due to ↑K+ and H+ secretion by the collecting duct.
• Electrolyte abnormalities are the result of blocking NKCC2 which effects other transporters in kidney.
• Hyperuricemia may be caused by hypovolemia enhancing uric acid reabsorption in the proximal tubule and may trigger flare-ups in people with gout.
• Rare hypersensitivity from sulfonamide may occur with loop diuretics except ethacrynic acid.

Loop Diuretics: Chemistry & Clinical Applications

• Several chemical structures are shown.
• To determine which drugs cause rare hypersensitivity, consider structures.

Thiazides & Thiazide-like Diuretics

• General: structurally similar and have the same MOA.
• Actively secreted into the PCT filtrate and carried to the DCT.
• Competes for the Cl- binding site within the Na+/CI- transporter (NCC) in DCT cells.
• Transporter-blocking inhibits Na+ and Cl- reabsorption (increasing excretion).
• Secondarily inhibits the target carbonic anhydrase, increasing HCO3 excretion and urine pH.
• Diuretics include: Hydrochlorothiazide (Esidrix)* and Chlorothiazide
• Thiazide-like Diuretics: Metolazone, Chlorthalidone, and Indapamide.

Thiazides/Thiazide-like Diuretics: Pharmacodynamics

• The sodium/chloride transporter target is in the distal convoluted tubule (DCT).

Thiazide/Thiazide-Like Diuretics: MOA & PD

• The drugs inhibit NaCl reabsorption from the luminal side (epithelial cells) of the distal convoluted tubule (DCT).
• These agents directly block the Na+/Cl- transporter (NCC).
• Increased Na+/Cl excretion, enhanced Ca2+ reabsorption (opposite to Loop Diuretics).
• The exchange leads to Ca2+ reabsorbed into the blood because the effect impacts water and volume depletion in the Proximal Tubule.

Thiazide Diuretics: SAR Map

• A thiazide (benzothiadiazine) is the pharmacophore.
• R2 = An electron-withdrawing group (EWG) at C6 (Cl, CF3) for diuretic activity.
• The sulfonamide (C7) group is essential for activity.
• R₁ = a lipophilic group (increases diuretic potency and duration of action).
• R3 = Alkyl substitutions (decreases hydrophilicity and increases the duration of diuretic action).
• Thiazide-like diuretics are bioisosteres of thiazides.

Thiazides/Thiazide-like Diuretics: Structures

• Several chemical structures of different drugs are shown.

Thiazides: HCTZ & Chlorothiazide

• General MOA & Information
  • Hydrochlorothiazide (HCTZ) is the thiazide prototype.
  • All Thiazides feature a weakly acidic (unsubstituted) sulfonamide group; essential for activity.
  • HCTZ is very potent and should be given at lower doses than chlorothiazide.
  • Chlorothiazide has poor lipophilicity and must be given in relatively large doses with parenteral formulations.
• Adverse Effects: see common thiazide/thiazide-like diuretics toxicities.
• Therapeutic Uses: Hypertension and heart failure

Thiazide-like Diuretics: Chlorthalidone & Indapamide

• General MOA & Info
  • Chlorthalidone and indapamide are common and have same MOA as thiazides.
  • Weakly acidic (unsubstituted) sulfonamide groups are essential for activity.
  • Chlorthalidone has a slower absorption rate and longer duration of action (DOA).
  • Indapamide has a long DOA and mainly goes via the biliary system.
• Adverse Effects: See common Toxicities for Thiazide/Thiazide-like Diuretics.
• Therapeutic Uses: Hypertension and heart failure

Thiazide/Thiazide-like Diuretics: PChem & PK

• Generally, water-soluble sodium salts prepared for IV administration, although given orally.
• Most thiazides excrete unchanged in the urine other than indapamide.
• Polarity drives hydrophilic interactions, especially with indapamide thiazide (extensively metabolized).

Thiazide/Thiazide-like Diuretics: Indapamide Metabolism

• A metabolic reactions map for Inapamide.

Thiazide/Thiazide-like Diuretics: Toxicity & Adverse Effects

• Associated with electrolyte imbalances.
• Hypokalemia and hypokalemic metabolic alkalosis.
• Hyponatremia (decreased Nat concentration).
• Electrolyte abnormalities block NCC, which effects transporters in the kidney.
• Increased uric acid production (hyperuricemia) and exacerbate gout.
• Hyperglycemia may occur (by decreasing insulin production) in patients who are diabetic or glucose tolerance abnormal; may cause new onset diabetes.
• Agents increase total serum cholesterol and/or LDL and cause hyperlipidemia.
• Rare hypersensitivity with thiazides relate to sulfonamide cross-reactivity.

Thiazide/Thiazide-like Diuretics: Toxicity & Adverse Effects

• Hyperglycemia may occur in patients who are diabetic or are glucose tolerance abnormal.
• Caused by stimulating ATP-sensitive K+ channels in beta cells of the pancreas.
• Leads to K+ hyperpolarization and inhibited insulin secretion.
• Is a dose-dependent the off-target toxicity.
• FYI, ATP-sensitive K+ channels are targeted by sulfonylureas and by insulin secretagogues (glyburide; nateglinide), which depolarize channels and increase secretion (good outcomes).

Thiazide/Thiazide-like Diuretics: Toxicity & Adverse Effects

• Thiazide and drugs here have sulfonamide functional groups.
• Sulfonamides lead to cross-reactivity and lead to rare hypersensitivity reactions, or allergic ones.
• Observed in 3% of general population (rare).
• Hypersensitivity is rare with thiazide, as sulfonamide antibiotics can affect more patients.

Thiazide & Loop Diuretics: DDIs with NSAIDs

• Rely on renal prostaglandins to reach the site of action (DCT).
• Vasodilator prostaglandins PGE2 and PGI2 promote glomerular filtration and blood flow in the kidney.
• NSAIDs bind COX1 and 2 leading to prostaglandin synthesis being inhibited completely.
• Reduces the efficacy of thiazides/loop diuretic effects by inhibiting renal prostaglandin.

Diuretics that Decrease Blood H+ Causes Alkalosis

• Loop diuretics cause decreased K+ and H+ in blood, related to hypokalemic metabolic alkalosis.
• Thiazides cause decreased K+ and H+ in blood, related to hypokalemic metabolic alkalosis.

Potassium Sparing Diuretics

• Potassium-sparing diuretics prevent K+ secretion while promote Na+ excretion.
• 2 mechanisms: 1. inhibition of Na+ influx through ion channels in luminal membrane 2. competitive antagonism of mineralocorticoid receptors.
• Hyperkalemia is a major adverse effect, avoid agents in patients with chronic renal insufficiency.

1A. Potassium Sparing Diuretics

• Non-MR antagonist potassium-sparing diuretics block Nat entry through epithelial Na+ channels (ENaC) in collecting tubules.
• These drugs are weak organic bases/inhibit the channel by binding to negatively charged regions.
• Direct Na+ secretion causes increased Na+ & Cl- excretion, reduces K+ secretion, reducing hypokalemia and effects.
• Specific drugs are amiloride and triamterene.

Potassium Sparing Diuretics: MOA & PD

• Directly interfere with Na+ entry by blocking the epithelial Na+ channel (ENaC) in the collecting tubule (MOA 1).
• K+ secretion couples with Na+ entry; ENaC blocking reduces K+ secretion in urine.
• MOA and PD differ from aldosterone antagonists, which block the effects of aldosterone in expressing Na+/K+ ATPase (MOA 2).
• Reduced K+ secretion for all potassium-sparing agents can lead to hyperkalemia, or an adverse effect.

1A. Potassium Sparing Diuretics: Weak Bases

• Amiloride and Triamterene are structures here.

• Structures have similar (pteridine and diazine) rings: no defined pharmacophore.

• Are weak bases to positively interact in the Na+ channel's regions.

• Na+ channel binding is pH dependent: stronger base amiloride (pKa = 8.7) is 100-fold more active than triamterene (pKa = 6.2).

• The Guanidino group (circled) makes amiloride a stronger base.

Potassium Sparing Diuretics: Amiloride & Triamterene

• Amiloride exhibits variable (30% to 90%) bioavailability while triamterene is well absorbed (moderate bioavailability of ~52%).
• Amiloride is excreted nearly equal in feces and urine unchanged.
• Triamterene is extensively metabolized by aromatic hydroxylation/sulfate conjugation with CYP1A2.
• Because triamterene undergoes extensive metabolization, it has a shorter half-life, and must be given more frequently that amiloride, which isn't metabolized.
• Hyperkalemia due to activity.
• Triamterene may precipitate in the urine, causing kidney stones, because it is only slightly soluble.
• Taking Triamterene combined with indomethacin may cause Acute renal failure.

Aldosterone Antagonists

• Block the activity of mineralocorticoid receptors (MR) late in the DCT and collecting duct (CD) of the nephron.
• Antagonists compete with aldosterone, interfere with Na+/K+ ATPase, and limit expression of epithelial sodium Na+ channel (ENaC).
• Action reduces Na+, Cl- and water reabsorption.
• Also act as diuretics by reducing potassium K+ secretion.
• Includes Spironolactone (Aldactone)* and Eplerenone.

Potassium Sparing Diuretics: MOA & PD

• Non-MR antagonists amiloride and triamterene directly interfere with Na+ entry, blocking epithelial Na+ channel (ENaC) in the collecting tubule (MOA 1).
• Since K+ secretion coupled with Na+ entry, ENaC reduces K+ secretion in urine.
• Differs form aldosterone antagonists who block effects of aldosterone and expressing Na+/K+ ATPase (MOA 2). Reduced K+ agents can lead to, and increase the risk of leading to hyperkalemia (adverse effect).

Aldosterone Antagonists: Spironolactone

Is a synthetic steroid analogue that antagonizes aldosterone competitively and is an agonist of MR.

• The steroid has a slow onset of action and requires several days for full effect.
• Adverse effects of hyperkalemia from K+ sparing activity.
• Gynecomastia in men and breast tenderness in women is common due to the steroid structure (similar to gonadal hormones); eplerenon appears to have reduced such effects.

Review: MR Agonist Aldosterone (Steroid Hormone)

• Steroids synthesize and bind to target sites.
• Steroid template with the structure shown.

1B. Aldosterone Antagonists: MOA & PD

• A mechanism pathway map is shown.

1B. Aldosterone Antagonists: SAR

• Spironolactone and eplerenone structures are similar to aldosterone analogs.
• Modifications to steroids that are similar to hormones like aldosterone lead to antagonism.
• 5C Lactone ring is required for binding to the mineralcorticoid receptor, antagonism/receptor blocking.
• Eplerone has an acetyl group at C-7 (instead of sulfoxide) and an epoxide group.

1B. Aldosterone Antagonists: Metabolism

• Both drugs undergo extensive metabolism and excrete in the urine and feces.
• Spironolactone becomes canrenone (~90%), which has metabolite activity.
• Eplerenone gets only metabolized to inactive metabolites.

1A&B: Potassium Sparing Diuretics: Adverse Effects

• Hyperkalemia is frequent.
• Range from mild or lethal; higher risk in patients with renal/ACEI issues, ARB, beta blocker, aliskiren, and/or using NSAIDs.
• Gynecomastia in men and breast tenderness in women with aldosterone antagonist spironolactone occur due to structure similarity to testosterone/progesterone respectively.

Diuretics: Pharmacology Study Tool

• A table showing "Diuretics: Pharmacology Study Tool" for Diuretic Classes, Specific Drugs, MOA, PD, Other Effects, Clinical Uses, Adverse Effects/Toxicity, and PK & Other Info.
• Blank information areas for Thiazide/Thiazide-like Agents, Loop Diuretics, Potassium Sparing and Mineralocorticoid Receptor Antagonists here.

ANTIPERTENSIVE: PRACTICE PROBLEMS

• Slide contains practice for applying knowledge to answer questions.

Diuretics Review Activity

Identify the Drug Class

• Relates to the nephron anatomy chart.
• ? on what to class the Acetazolamide.

Mini Case: Diuretics

• Mr. H is taking a thiazide to treat hypertension and ibuprofen for headaches/back pain;
• Questions address the thiazide site of action, ibuprofen/Ibuprofen pain relief, and negative issues from taking them together.

Concept Map Puzzle: Diuretics

• The words include: K+ Sparing Drug, ethacrynic acid, derivatives drugs, NCC Transporter, MR antagonists, thiazides drugs, drugs the produce the benzoic acids loop, hydrochlorothiazide, drugs that enhance blood volume with a bumetanide, basic for all with Gynecomastia Spironolactone, Triamterene loop diuretics, and Basic ENaC Blockers.

Other Information

• Drugs to Describe General Actions/MOAs of Therapeutics, distinguish classes of therapeutics by its structure activity relationship and relate structure function, describe specific effects to class, show groups, and receptors that therapeutic will bind and all physiochemical properties impact therapeutic.
• Highlight these key aspects on therapeutic actions.
• Several antihypertensive made this list like Chlorthalidone (Thalitone), Frusemide (Lasix), (The Thiazide), HCTZ (Esidrix), Spironolactone (Aldactone), and Trimterene/ HCTZ (Dyazide).

This lesson covers how diuretics manage hypertension, kidney functions, and the impact of salt levels. It also discusses drug mechanisms, physiochemical properties, and the structure-activity relationship of diuretic medications.