Pharmacy Chapter on Cardiovascular Drugs

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Questions and Answers

What is the primary mechanism of action of carbonic anhydrase inhibitors like acetazolamide?

Inhibition of the renal carbonic anhydrase enzyme (correct)

Inhibition of sodium-potassium pumps in the loop of Henle

Blockade of aldosterone receptors in the collecting duct

Inhibition of water reabsorption in the proximal convoluted tubule

Which class of diuretics is specifically known for acting on the Thick Ascending Loop of Henle?

Osmotic diuretics

Potassium-sparing diuretics

High-ceiling or loop diuretics (correct)

Thiazides and Thiazide-like diuretics

What effect do potassium-sparing diuretics have on the renal system?

Increased reabsorption of sodium and water

Inhibition of the natural production of diuretic hormones

Inhibition of sodium reabsorption while conserving potassium (correct)

Extrusion of potassium from the renal tubules

What is a common effect observed with osmotic diuretics like mannitol?

Increased urine output due to osmotic pressure Signup and view all the answers

Which mechanism contributes to the diuretic effect observed after using thiazides like hydrochlorothiazide?

Inhibition of sodium reabsorption in the distal convoluted tubule Signup and view all the answers

What is the essential component necessary for the inhibition of carbonic anhydrase by sulfonamides?

A sulfamoyl group Signup and view all the answers

Which derivative of heterocyclic sulfonamides is noted for being a more potent inhibitor of carbonic anhydrase?

Methazolamide Signup and view all the answers

Among the heterocyclic sulfonamides, what characteristics are associated with the derivatives that exhibit the greatest CA-inhibitory activity?

Highest potency coefficient (PC) and lowest pKa Signup and view all the answers

What structural feature is critical for retaining diuretic activity in the sulfamoyl derivatives?

Unsubstituted nitrogen in the sulfamoyl group Signup and view all the answers

What is a primary purpose of using diuretics in clinical settings?

To alkalinize urine for excreting weak acids Signup and view all the answers

Which of the following compounds is known as a precursor to thiazide diuretics?

Dichlorophenamide Signup and view all the answers

What mechanism do diuretics primarily utilize to exert their effects?

Inhibiting tubular reabsorption of electrolytes Signup and view all the answers

In the context of meta-disulfamoylbenzene derivatives, what functional group is shown to be effective in their chemical structure?

A sulfonamide group Signup and view all the answers

What is the primary mechanism of action of thiazides and thiazide-like diuretics?

Blocking the Na+/Cl- cotransporter in the distal convoluted tubule Signup and view all the answers

Which factor influences the difference in potency among thiazide diuretics?

The lipophilicity of the substituent at position 3 Signup and view all the answers

What distinguishes potassium-sparing diuretics from other diuretics?

They inhibit sodium reabsorption without promoting urinary potassium loss Signup and view all the answers

Which thiazide diuretic is noted for having the lowest absorption rate?

Chlorthiazide Signup and view all the answers

What factor primarily dictates the duration of action of thiazide diuretics?

The lipophilicity of the drug and plasma binding Signup and view all the answers

Which characteristic is common to most thiazide diuretics?

High luminal fluid concentrations achieved through glomerular filtration Signup and view all the answers

In which part of the nephron do thiazide diuretics primarily exert their effect?

Distal convoluted tubule Signup and view all the answers

What structural feature is characteristic of thiazide and thiazide-like diuretics?

Absence of a double bond between positions 3 and 4 Signup and view all the answers

Which of the following is a representative thiazide-like diuretic?

Metolazone Signup and view all the answers

Which diuretics act specifically in the collecting duct?

Aldosterone antagonists Signup and view all the answers

What is the typical onset time for thiazide diuretics once administered?

1-2 hours Signup and view all the answers

Which thiazide diuretic is primarily used for its potassium-sparing effect?

Spironolactone Signup and view all the answers

What is the common mechanism of action of pteridines and aminopyrazines?

They inhibit sodium reabsorption Signup and view all the answers

Which of the following is true regarding the pharmacokinetics of thiazides?

Most drugs in this class are extensively protein bound Signup and view all the answers

Study Notes

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).

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Description

This quiz covers essential information from Foye's Principles of Medicinal Chemistry and Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry related to drugs and diseases of the cardiovascular and renal systems. Focus on drugs for hypertension and their classifications, including antihypertensives and diuretics.