Pharmacy Chapter on Cardiovascular Drugs

Textbooks

• Foye's Principles of Medicinal Chemistry, 7th edition, Chapter 37 is a relevant textbook
• Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th edition, Chapter 10 is also a relevant textbook

Drugs and Diseases of the Cardiovascular/Renal Systems

• The topic is Drugs and Diseases of the Cardiovascular/Renal Systems
• This is the first lecture on the topic

General Information

• Lecturer: Dr. Aaron Muth
• Email: [email protected]
• Office: St. Albert Hall, Room B26
• WebEx Room: https://sju.webex.com/meet/mutha
• Office hours: Mondays and Thursdays, 10 am to 11:30 am, or by appointment

Drugs for the Treatment of Hypertension

• The topic is Drugs for the Treatment of Hypertension

Overview of Antihypertensives

• Diuretics: Carbonic anhydrase inhibitors, High-ceiling or loop diuretics, Thiazides and thiazide-like diuretics, Potassium-sparing diuretics, Osmotic diuretics
• Angiotensin-converting enzyme inhibitors (ACEIs)
• Angiotensin II receptor antagonists (ARBs)
• Sympatholytics: β-adrenergic blocking agents, Centrally acting alpha-agonists, Adrenergic neuron blockers, α-adrenergic blockers
• Calcium-channel blockers (CCBs)
• Vasodilators

Diuretics (Detailed)

• Definition: An agent increasing urine formation, primarily by decreasing Na+ ion and water reabsorption from kidney tubules.
• Major Uses: Mild hypertension, Treating edema caused by congestive heart failure (CHF), Treating edema caused by renal and liver disorders
• Kidney Functions: Regulate volume and composition of body fluids; maintain body fluid pH; eliminate water-soluble metabolic waste
• Nephron: Basic functional unit of the kidney, consisting of three parts: glomerulus (enclosed in Bowman's capsule), renal tubule (proximal convoluted tubule (PCT), 3 segments (S1, S2, S3), loop of Henle, descending limb (DLH), thick ascending limb (TALH), and distal convoluted tubule (DCT)), collecting tubule
• Classification based on their site of action: Proximal Convoluted Tubule (PCT), Carbonic anhydrase inhibitors – acetazolamide, Osmotic diuretics – mannitol, urea, Thick Ascending Loop of Henle (TALH), High-ceiling or loop diuretics – Furosemide, Distal Convoluted Tubule (DCT), Thiazides and Thiazide-like diuretics – Hydrochlorothiazide, Collecting Duct (CD), Potassium-Sparing Diuretics - Spironolactone
• PCT Diuretics (Carbonic Anhydrase Inhibitors): Sulfanilamide originally introduced as an antibacterial, observed to produce a mild diuresis by inhibiting renal carbonic anhydrase. Carbonic anhydrase catalyzes CO2 hydration to carbonic acid, which dissociates into H+ and HCO3-.
• SAR Studies: Sulfanilamide was used as a lead compound, SAR studies demonstrated that the sulfonamide N must be unsubstituted for diuretic activity
• Mechanism of inhibition: Similarity in structure between carbonic acid and the sulfamoyl group of sulfanilamide leads to competitive binding at the carbonic anhydrase active site.
• Binding Sites: Binding of carbonic anhydrase and sulfonamide at the hypothetical enzyme active site.
• Diuretics (Continued): Adverse effects include: Metabolic acidosis, Hypokalemia, Sulfonamide-like hypersensitivity reactions (e.g., uticaria, drug fever, blood dyscrasias).
• DCT Diuretics (Thiazides and Thiazide-like Diuretics): Developed from meta-disulfamoylbenzenes as diuretics
• Cyclization: When an amide substituent was introduced to chloraminophenamide, it could be cyclized to form chlorothiazide. A new class of diuretics (1,2,4-benzothiadiazine-1,1-dioxides, or thiazides) emerged.
• Hydrothiazides: Cyclization with aldehydes or ketones leads to dihydro derivatives (hydrothiazides).
• Structure-Activity Relationships: The sulfonamide group at position 7 is essential for CA activity and must remain unsubstituted, electron-withdrawing group at position 6 is necessary.
• SAR continued: Substitution at positions 4, 5, or 8 decreases activity; saturation of the 3, 4 double bond increases diuretic activity; lipophilic substitution at position 3 increases activity along with duration of action; alkyl substitution at position 2 increases the duration and decreases polarity; position 1 can be a sulfonyl or carbonyl.
• Products (Thiazide Analogues): Chlorothiazide (Diuril®), Benzthiazide (Exna®)
• Products (Hydrothiazide Analogues): Hydrochlorothiazide (Hydrodiuril®), Hydroflumethiazide (Saluron®), Bendroflumethiazide (Naturetin®), Trichlormethiazide (Naqua®), Methyclothiazide (Enduron®), Polythiazide (Renese®), Cyclothiazide (Anhydron®).
• Representatives from Thiazide-like Diuretics: Mefruside (Baycaron), Xipamide (Aquaphor, Diurexan), Clopamide (Aquex, Brinaldix), Indapamide (Lozol)
• Representatives from Thiazide-like Diuretics: Quinethazone (Hydromox), Metolazone (Diulo, Zaroxolyn), Clorexolone (Nefrolan), Chlorthalidone (Hygroton, Thalitone)

Pharmacokinetics

• Most thiazides and thiazide-like drugs are well absorbed orally except for chlorthiazide (10%).
• Rapid onset (1-2 hrs)
• Peak effect is between 3-6 hrs.
• Extensive protein binding
• High luminal fluid concentrations achieved by glomerular filtration and transport by OATS in the proximal tubule.
• Inhibiting Na+/Cl- co-transport system.

Mechanism of action

• Thiazides and thiazide-like diuretics block sodium ion reabsorption in the distal convoluted tubule by blocking the Na+/Cl- cotransporter.

CD Diuretics (Potassium Sparing Diuretics)

• Three chemically distinct diuretics acting at CD:
  • Aldosterone antagonists
  • Pteridines
  • Aminopyrazines
• Inhibit sodium ion reabsorption without promoting urinary potassium loss, referred to as potassium-sparing diuretics.

Pteridines and Aminopyrazines

• Triamterene (Dyrenium) and amiloride (Midamor) inhibit sodium ion reabsorption at the CD site via a mechanism distinct from aldosterone antagonism. This involves plugging of Na+ channels in the luminal membranes.

Diuretics (Continued)

• Triamterene and amiloride are weak organic bases, reaching luminal fluid through glomerular filtration and active tubular secretion (OCTS).
• The most serious side effect is hyperkalemia, thus potassium supplements are contraindicated.
• Triamterene uniquely contributes to kidney stone formation and is contraindicated in patients with impaired renal function.
• Often used in conjunction with site 2 or 3 diuretics to improve diuresis and prevent potassium loss.

Calcium Channel Blockers (Introduction)

• Role of calcium in muscle contraction: Cytosolic calcium binds to troponin C (cardiac) or calmodulin (smooth muscle), uncovering myosin binding sites on the actin molecule, resulting in muscle contraction.
• Mechanism of calcium movement and storage: Receptor-operated channels, Na+/Ca2+ exchange, leak processes, potential-dependent channels (voltage dependent),ATP-dependent calcium pump,Mitochondrial storage, Sacroplasmic reticulum storage
• Sites 1 and 4 are primary channels.

Calcium Channel Blockers (SAR)

• Chemical classification: 1,4-dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem).
• 1,4-Dihydropyridines are the majority of this drug class (e.g. Nifedipine)

Calcium Channel Blockers (SAR of 1,4-DHPs)

• 4-phenyl is necessary, with pyridine or cycloalkyl substituents that keep rings perpendicular at positions X.
• Essential 1,4-DHP along with pyridine or piperidine at other positions.
• Esters optimize activity where C3-carbonyls are synplanar and C5-carbonyls are antiperiplanar.
• Aminoethanol ether (e.g., amlodipine) enhances solubility (salt formation) and increases potency. The cis arrangement of the acetyl ester and phenyl ring is crucial for diltiazem's activity.

Structure Challenge (Calcium Channel Blockers)

• Presents a list of chemical structures for Calcium Channel Blockers (Nifedipine, Felodipine, Amlodipine, Nimodipine, Nisoldipine, Isradipine, and Nicardipine).

Calcium Channel Blockers (Physicochemical Properties)

• All chemical classes are basic with 1,4-DHPs being less basic, except for amlodipine and nicardipine.
• At physiological pH, 1,4-DHPs are unionized while others are ionized.
• 1,4-DHPs are lipophilic with good oral bioavailability, lipophilicity increased by larger esters and aromatic substitution in the phenyl groups.
• All except nifedipine contain at least one chiral carbon.
• S-enantiomer of verapamil is more potent.
• Cis arrangement of the acetyl ester and the phenyl ring is essential for diltiazem.

Calcium Channel Blockers (Metabolism)

• All undergo extensive first-pass metabolism.
• N-demethylation, hydrolysis and/or hydroxylation are common metabolic pathways.
• Some drug metabolism can be significantly reduced by grapefruit juice (e.g. Nifedipine).