Antihypertensives: Diuretics, MR Antagonists, Vasopressin Antagonists

Drug Classifications and Mechanisms of Action

Antihypertensive drugs are classified based on their mechanism of action. These include:

1. Sympatholytic Drugs – Calm the nervous system to lower blood pressure.

• Centrally acting drugs – Work in the brain to reduce signals that raise BP.

• Ganglionic blockers – Block nerve signals in the autonomic system.

• Adrenergic neuron blockers – Stop nerves from releasing BP-raising chemicals.

• Beta-blockers (β₁/β₂ blockers) – Slow heart rate and reduce the force of the heart.

• Alpha-1 blockers – Relax blood vessels so blood flows more easily.

• Mixed alpha/beta blockers – Do both: slow heart + relax blood vessels.

2. Calcium Channel Blockers – Relax blood vessels and reduce heart workload.

• Dihydropyridines – Mostly work on blood vessels (e.g., amlodipine).

• Non-dihydropyridines (like verapamil, diltiazem) – Also affect the heart.

3. Vasodilators – Directly relax blood vessels.

• Arterial only – Work mainly on arteries.

• Arterial and venous – Work on both arteries and veins.

4. ACE Inhibitors – Block the enzyme that makes angiotensin II (a BP-raising hormone).

5. ARBs (Angiotensin Receptor Blockers) – Block angiotensin II from working.

6. Diuretics – Help the body get rid of extra salt and water to lower BP.

Learning Objectives for Fluid Volume Control Drugs

For diuretics, mineralocorticoid receptor (MR) antagonists, and vasopressin antagonists, it is important to understand their:

• Chemotypes

• Physicochemical properties

• SAR (Structure-Activity Relationship)

• PK (Pharmacokinetics)

Diuretics: Definition, Use, and Mechanism

Diuretics increase the rate of urine formation, thereby reducing water volume in the body.

• They ideally have no effect on the reabsorption of essential substances like proteins, vitamins, glucose, or amino acids.

• A consequence of diuresis can be increased excretion of sodium (Na^+), potassium (K^+), and chloride (Cl^−).

  • Saluresis refers specifically to Na^+ and Cl^− excretion.

• Diuretics are therapeutically useful in treating:

  • Edema (excessive extracellular fluid): Reducing fluid alleviates the workload on the heart.

  • Hypertension (high blood pressure): Decreasing blood volume reduces the amount of blood the heart must pump.

• Solvation shell formation is vital for maintaining constant osmolarity in body compartments.

  • Water molecules migrate to meet with ions, forming solvation shells (ion–dipole interaction).

  • Sodium's solvation shell is notably stable and well-ordered, with 6–8 water molecules per sodium ion (H2O/Na^+).

  • Water molecules are tightly bound to Na^+, so "where the Na^+ goes, the waters follow!".

The Nephron and Diuretic Sites of Action

The nephron is the functional unit of the kidney, and diuretics act at various sites along its length. Key parts include:

• BC: Bowman’s capsule

• CD: Collecting duct

• DCT: Distal convoluted tubule

• DLH: Descending limb of the Loop of Henle

• G: Glomerulus

• PCT: Proximal convoluted tubule

• PST: Proximal straight tubule

• TALH: Thick ascending limb of the Loop of Henle

Diuretics, MR antagonists, and Vasopressin antagonists include:

• Carbonic Anhydrase Inhibitors: Acetazolamide (Diamox®), Brinzolamide (Azopt®)

• Loop (High-Ceiling) Diuretics: Furosemide (Lasix®), Bumetanide (Bumex®), Torsemide (Demadex®), Ethacrynic Acid (Edecrin®)

• Thiazide Diuretics: Hydrochlorothiazide (Microzide®), Chlorothiazide (Diuril®)

• Thiazide-Like Diuretics: Metolazone (Zaroxolyn®), Indapamide (Lozol®), Chlorthalidone (Thalitone®)

• Potassium-Sparing Diuretics: Triamterene (Dyrenium®), Amiloride (Midamor®)

• MR Antagonists: Spironolactone (Aldactone®), Eplerenone (Inspra®)

• Vasopressin Antagonists: Tolvaptan (Samsca®), Conivaptan (Vaprisol®)

• Osmotic Diuretics: Sorbitol, Mannitol, Isosorbide

Carbonic Anhydrase (CA) Inhibitors

Carbonic anhydrase (CA) catalyzes the interconversion of carbon dioxide + water and carbonic acid (H2CO3).

• The conjugate base form of carbonic acid (pKa1 = 6.35) is bicarbonate (HCO3^−).

• Inhibition of CA in the proximal convoluted tubule provides a mechanism to alkalize the urine, due to:

  • Increased H^+ absorption

  • Decreased H^/Na^+ exchange by sodium–hydrogen antiporter 3 (NHE3)

  • Increased Na^/HCO3^− in urine

  • Increased H2O excretion (via hydration shell formation)

• Prolonged use carries a risk of causing metabolic acidosis.

SAR of Carbonic Anhydrase Inhibitors

• An unsubstituted sulfonamide is required.

• The acidity of the sulfonamide enhances binding to CA Zn^{2+}.

• To produce meaningful diuresis, 99% inhibition of CA is needed.

• Acetazolamide is orally active.

• Prolonged use leads to more alkaline urine and more acidic blood (acidosis).

• Primary use is ocular (glaucoma) and it is also used as an anticonvulsant.

• Since they are sulfonamides, there is a risk of hypersensitivity in patients who are allergic to sulfonamide antimicrobials

Clinical Note

• Ammonia reabsorption in the renal tubules increases as a result of urinary alkalinization.

Benzothiadiazide (Thiazide) Diuretics

Mechanism

• Logical SAR studies on carbonic anhydrase inhibitors led to this class of compounds.

• Benzothiadiazides were not potent CA inhibitors.

• They act by a different mechanism.

• The major site of action is the distal convoluted tubule (DCT).

• They compete for chloride at the Na^/Cl^− cotransporter (NCC) and thus inhibit re-absorption of Na^+.

• They are saluretics, leading to salt excretion.

• As sulfonamides, there is a risk of hypersensitivity in patients who are allergic to sulfonamide antimicrobials.

Examples

• Chlorothiazide (Diuril®)

• Hydrochlorothiazide (Hydrochlorothiazide)

Hydrochlorothiazide (HCT)

• Is probably the most widely-used, orally bioavailable benzothiadiazide diuretic

• Does not undergo any metabolism; eliminated by the kidney unchanged.

Benzothiadiazide SAR

A-Ring SAR:

• All have the addition of another sulfonamide at C-7 (less acidic than the ring sulfonamide NH).

• Removal or replacement of this group greatly diminishes activity.

• Electron-withdrawing group at C-6, such as Cl or CF3, increases activity.

• Electron-donating group at C-6, such as methyl or methoxy, decreases activity.

B-Ring SAR: (Thiadiazine ring)

• N-2 NH sufficiently acidic to yield water-soluble solutions → IV administration if necessary.

• Substitution at C-3 is allowed with a variety of groups, and often yields increased activity.

• When C-3 substituent is chloromethyl or phenylmethyl, lipophilicity is increased as is duration of action.

• The B-ring C3–N4 bond can be a single bond or a double bond.

Structurally-Related Thiazide-Like Diuretics

A-Ring:

• Substituents are the same as HCT and other thiazide diuretics

B-Ring:

• May be missing. Substituents show both similarities and differences with thiazides

Metolazone (Zaroxolyn® , Mykrox®)

• Quinazolin-4-one—structurally similar to benzothiadiazides

• Carbonyl replaces SO2 (bioisosteric)

• Marketed as the racemate

• Long-acting (once-daily oral medication); highly protein bound

• Minimal metabolism

Indapamide (Lozol®)

• Indapamide is an indoline chemotype (indole in which the C2–C3 bond has been reduced)

• Only one sulfonamide in the molecule

• Extensively metabolized by CYP3A4 and CYP2C9/19

Chlorthalidone (Thalitone®)

• Exists as racemic phthalimidine form

• Long-acting: t1/2 40–60 h (substantially protein-bound: 75%)

• Minimal metabolism: ~70% excreted in urine and feces unchanged

• As sulfonamides, there is a risk of hypersensitivity in patients who are allergic to sulfonamide antimicrobials

Loop (High-Ceiling) Diuretics

Mechanism

• Related more by pharmacological similarities (how they act) than structural similarities (how they look)

• Produce more profound peak diuresis, hence the term “high ceiling”

• They act in the thick ascending limb of the loop of Henle

• Inhibit the Na^/K^/2Cl^−− symporter NKCC2

• Promote excretion of sodium, potassium, chloride, magnesium and water

SAR

• Anthranilic acid derivative (5-sulfamoylanthranilates) or similar analogs.

• Structurally related to “thiazides” with similar functionality: chlorine and sulfonamide (sulfamoyl group) on benzene ring

• Carboxyl group is acidic, improves water solubility, and likely metabolic stability

• Furosemide is orally bioavailable, but may be used parenterally

• Hypokalemia is a risk, as with “thiazides”, so it may be administered with a K^+ supplement or a potassium-sparing diuretic

Structural comparison

• Furosemide, bumetanide, and torsemide all have a sulfonamide group

  • This will be a potential concern for patients who are allergic to sulfonamides (sulfa allergy)

• Ethacrynic acid does not possess a sulfonamide

  • It has a carboxylic acid on one end, and an enone on the other end

  • This is an option for a patient that has a sulfonamide (sulfa) allergy

  • It is metabolically deactivated by conjugation with glutathione [ECG] (addition to the enone)

Potassium-Sparing Diuretics

Mechanism

• Exert a mild diuretic effect

• Triamterene and amiloride directly block epithelial sodium channel (ENaC) in principal cells of the late distal convoluted tubule and collecting duct

• Mineralocorticoid receptor (MR) antagonists compete with aldosterone at its receptor in the nucleus to prevent activation of ENaC channels

• Block reabsorption of sodium and inhibit secretion of potassium

• Therefore, used to offset effects of diuretics that result in loss of potassium

Structural Features

• Both have pyrazine rings

• Weak bases: exert effects in a pH- and voltage-dependent manner

• Amiloride is a stronger base (pKa = 8.7) than triamterene (pKa = 6.2), therefore more extensively protonated at physiological pH

Mineralocorticoid Receptor (MR) Antagonists

• MR is a nuclear transcription factor

• MR antagonists synonymous with aldosterone antagonists

• Aldosterone, a potent mineralocorticoid receptor agonist, is secreted in the adrenal cortex

  • Promotes NaCl and H2O retention

  • Promotes K^+ and H^+ excretion

• MR antagonists promote NaCl and water excretion and reduce K^+ excretion (potassium-sparing)

• Act in the kidney at the late distal convoluted tubule and collecting system

SAR

Note the conversion of α-hydroxy ketone in aldosterone (agonist) to the γ-lactone at C-17 in spironolactone and eplerenone (antagonists)

Spironolactone (Aldactone®)

• Is a competitive MR inhibitor (binds to the same site as aldosterone)

• The γ-lactone on the D-ring is an essential feature for antagonist activity

• Carbon attached at C-17 is alpha

  • Opposite orientation to aldosterone, which is beta

• The C-18 carbon atom is a methyl substituent (in contrast to aldosterone’s aldehyde)

• The C-7 thioacetyl (S-acetyl) group on the B-ring enhances activity; disrupts activation of MR and subsequent transcription

• Well-absorbed orally (90%)

• Extensively metabolized by first-pass in liver to major active metabolites canrenone, 7α-thiomethylspironolactone, and 6β- hydroxy-7α-thiomethylspironolactone. In addition to being active, these metabolites may also be hepatotoxic.

Eplerenone (Inspra®)

• Improved selectivity over spironolactone versus other nuclear hormone receptor (NHR) targets

  • This was the specific objective of the new SAR

• Adds a Δ9-11 epoxide at carbons 9 and 11

• Acetate replaces thioacetate

  • Relatively more stable, does not undergo elimination

  • Bound to steroid nucleus through carbonyl carbon instead of a heteroatom

• Good oral bioavailability (70%) due to limited first-pass metabolism

  • Remember we’re looking at the net effects of absorption and metabolism

• CYP3A4-mediated metabolism, to inactive hydroxy metabolites.

  • Therefore, must be cautious when co-administering a CYP3A4 inhibitors (e.g., ketoconazole or erythromycin)

• As with spironolactone, hyperkalemia is an issue

• Reduced adverse events relative to spironolactone (more selective)

Vasopressin Antagonists

• Arginine vasopressin (AVP) is also known as the antidiuretic hormone (ADH):

  • Cys^1-Tyr^2-Phe^3-Gln^4-Asn^5-Cys^6-Pro^7-Arg^8-Gly^9-NH2

• Regulates body fluid osmolality—electrolyte/water balance

• V2 receptors are in the basolateral membrane of the collecting tubule cells in the kidney

  • V2 activation results in insertion of aquaporins (water channels) into the apical membrane, allowing water to easily permeate the membrane

• Currently-used vasopressin antagonists:

  • Tolvaptan (orally bioavailable antagonist)

  • Conivaptan (intravenous antagonist)

• Aquaretics (excretion of water without electrolytes)

• Used primarily to treat hyponatremia

SAR

• Chemotype: Benzazepine amides

• Benzo ring unsubstituted or substituted with Cl

• Azepine ring substituted with electron-donating, H-bonding group

  • Either hydroxyl or fused imidazole

• p-aminobenzoic acid amide on the benzazepine nitrogen

• p-amino group further acylated with an ortho- substituted benzamide

  • o-substituent can be either methyl or phenyl

Osmotic Diuretics

• Low-MW compounds used in small amounts as low-calorie sweeteners

• Poorly-absorbed orally

  • Administered intravenously, but used orally in larger amounts as osmotic laxatives

• Not metabolized

• Freely-filtered into renal tubules

• Increase osmotic pressure, causing water to pass into proximal tubule

• Thus, increase volume of urine (water + electrolytes)

• Not re-absorbed

Natrium and Kalium

• Natrium is the original Latin name for sodium

• Kalium is the original neo-Latin name for potassium

• The terms natremia and kalemia refer to issues of sodium and potassium in the blood:

  • Hyponatremia (low sodium)

  • Hypernatremia (high sodium)

  • Hypokalemia (low potassium)

  • Hyperkalemia (high potassium)

Origins of Diuretics

• Sulfanilamide is bioisosteric for p-aminobenzoic acid (PABA)

• PABA is an intermediate in bacterial folate biosynthesis

• Sulfanilamide rendered the urine of dogs alkaline (basic)

• They deduced this was through carbonic anhydrase

• This occurs by exchange of H+ for Na+ in the renal tubule

• Diuresis results from excretion of Na^+, HCO3^−, and water

Classes of diuretics

• Acetazolamide carbonic anhydrase inhibitors 1954

• Hydrochlorothiazide thiazides 1958

• Furosemide loop diuretics 1964

Sulfur Oxidation States

The lecture covers sulfur oxidation states relevant to various diuretic compounds and their structures

Thiazide Diuretics

The lecture provides a table summarizing the pharmacologic and pharmacokinetic properties of various thiazide diuretics

Thiazide-Like Diuretics

Lecture includes a table summarizing the pharmacokinetic properties for Thiazide-Like Diuretics

Nonthiazide Diuretics

The lecture includes a table summarizing the pharmacokinetic properties for Nonthiazide Diuretics