Angiotensin II and Hypertension Quiz

<p>Hydrophilic nature (C)</p> Signup and view all the answers

<p>Increases inhibitory potency (A)</p> Signup and view all the answers

<p>Enhanced ligand rigidity (C)</p> Signup and view all the answers

<p>It contributes to desolvation effects (C)</p> Signup and view all the answers

<p>By enhancing specific interactions (D)</p> Signup and view all the answers

<p>It exists as a di-zwitterion with equal charges. (A)</p> Signup and view all the answers

<p>R1 with a tetrazole functional group. (D)</p> Signup and view all the answers

<p>It provides enhanced lipophilicity and similar electronic configurations. (A)</p> Signup and view all the answers

<p>EXP-3174, a noncompetitive receptor antagonist. (C)</p> Signup and view all the answers

<p>Compound (b), which contains the 1,4-dihydropyridine ring. (A)</p> Signup and view all the answers

<p>Hyperlipidemia. (A)</p> Signup and view all the answers

<p>High-density lipoproteins (HDLs) (C)</p> Signup and view all the answers

<p>Inhibiting angiotensin-converting enzyme (ACE) (C)</p> Signup and view all the answers

<p>To convert 3-hydroxy-3-methylglutaryl (HMG)–CoA to mevalonic acid (A)</p> Signup and view all the answers

<p>Atorvastatin (B)</p> Signup and view all the answers

<p>Vasoconstriction of blood vessels (C)</p> Signup and view all the answers

<p>Two carboxylate groups and a secondary amine (C)</p> Signup and view all the answers

<p>Sulfhydryl-containing, Dicarboxylate-containing, and Phosphonate-containing inhibitors (D)</p> Signup and view all the answers

<p>They remain non-ionized (D)</p> Signup and view all the answers

<p>It contains a 6-hydroxyl group. (C)</p> Signup and view all the answers

<p>It enhances lipophilicity by converting carboxylic acids to esters (C)</p> Signup and view all the answers

<p>Inhibit cholesterol absorption (A)</p> Signup and view all the answers

<p>Skin rashes and taste disturbances (D)</p> Signup and view all the answers

<p>It is approximately 10-fold more potent (A)</p> Signup and view all the answers

<p>Stereochemistry of the lactone ring (C)</p> Signup and view all the answers

<p>It carries no charge (D)</p> Signup and view all the answers

<p>Addition of p-fluoro groups and hydroxyl groups (A)</p> Signup and view all the answers

<p>Increased aldosterone release (C)</p> Signup and view all the answers

<p>It improves gastrointestinal absorption and bioavailability (A)</p> Signup and view all the answers

<p>It decreases, reducing the amine's basicity (C)</p> Signup and view all the answers

<p>Increased susceptibility to metabolism (B)</p> Signup and view all the answers

<p>Enhanced hydrophilicity (C)</p> Signup and view all the answers

<p>Vasodilation of peripheral blood vessels (D)</p> Signup and view all the answers

<p>Neutral due to the zwitterion form (C)</p> Signup and view all the answers

<p>It decreases bioavailability (B)</p> Signup and view all the answers

<p>Esterase enzymes convert enalapril to enalaprilat in vivo. (C)</p> Signup and view all the answers

<p>Phosphinic acid, sulfhydryl, and carboxylate groups (B)</p> Signup and view all the answers

<p>Compound (d) lacking a carboxylic acid at the N-ring (B)</p> Signup and view all the answers

<p>They enhance the interaction profile with additional hydrophobic interactions. (C)</p> Signup and view all the answers

<p>It maintains its hydrophilic nature while facilitating absorption. (A)</p> Signup and view all the answers

<p>Enalapril requires activation by enzymes in vivo. (C)</p> Signup and view all the answers

<p>Presence of a carboxylic acid at the N-ring (C)</p> Signup and view all the answers

<p>Conversion occurs rapidly in vivo upon IV administration. (C)</p> Signup and view all the answers

Enalaprilat's ability to bind to ACE more effectively than captopril is because it better mimics the transition state of angiotensin I hydrolysis. This leads to stronger interactions with the enzyme and increased potency.

Replacing the imidazole ring of Histidine in angiotensin I with a methyl group in enalaprilat reduces desolvation effects, increasing affinity. The imidazole ring, being hydrophilic, causes desolvation without valuable interactions. Replacing it with a lipophilic methyl group reduces desolvation and improves ligand-protein recognition.

Replacing the isobutyl chain of Leucine in angiotensin I with a pyrrolidine ring in enalaprilat makes the ligand more rigid. This rigidity improves ligand recognition and enhances the affinity of enalaprilat compared to the natural substrate.

Angiotensin II is a potent vasoconstrictor that elevates blood pressure through the renin-angiotensin pathway. Strategies to counter its effects aim to disrupt this pathway at different points, using approaches like ACE inhibitors, Angiotensin II receptor blockers, or renin inhibitors.

High Angiotensin II levels contribute to hypertension through two primary mechanisms. The immediate effect is vasoconstriction, leading to increased blood pressure. In the long term, Angiotensin II stimulates aldosterone release, which promotes water and electrolyte retention, increasing blood volume and causing sustained high blood pressure.

ACE inhibitors can be categorized into three groups based on their chemical structure: sulfhydryl-containing (e.g., captopril), dicarboxylate-containing (e.g., enalapril), and phosphonate-containing (e.g., fosinopril). These different groups have unique properties and effects.

The sulfhydryl group in captopril contributes to its potent inhibitory activity but also causes two common side effects: skin rashes and taste disturbances, such as metallic taste or loss of taste. Additionally, the sulfhydryl group makes captopril susceptible to metabolism and has a shorter half-life due to the formation of disulfide dimers.

Enalaprilat is approximately 10 times more potent than captopril due to its conversion into a more active form, enalapril, in the body. Enalaprilat's metabolic processing differs from captopril, leading to a higher concentration of the active compound within the body.

Lisinopril, despite being highly hydrophilic, can pass through the lipid bilayer due to its di-zwitterionic form in the duodenum. This form has two positive charges and two negative charges, allowing internal binding and overall neutrality.

In angiotensin receptor blockers (ARBs), replacing the R1 group at the ortho position with a tetrazole functional group significantly enhances activity. This results in a compound like Losartan, where the tetrazole ring contributes to increased activity.

The tetrazole ring is a suitable bioisostere for the carboxylic acid functional group because it shares similar electronic and steric properties. Moreover, the tetrazole increases lipophilicity compared to carboxylic acid, enhancing bioavailability.

EXP-3174 is the active metabolite of Losartan, formed by the oxidation of its hydroxy methyl group to carboxylic acid. This metabolite is significantly more potent than Losartan, being 10-40 times stronger in receptor antagonism.

Compound (b) is the active agent among the provided compounds based on the structure-activity relationship (SAR) of calcium channel blockers. The presence of the 1,4-dihydropyridine (DHP) ring is essential for activity. Modifications like substitutions at N1 or the reduced pyridine ring significantly reduce or abolish activity.

Enalapril is a prodrug, meaning it's inactive when you take it. It needs to be converted into the active form, enalaprilat, by enzymes like esterases. These enzymes are found in the body but not in test tubes, so enalapril appears much less effective in lab tests. However, when injected into the body, it quickly gets converted, leading to similar effects as enalaprilat.

The phosphinic acid, sulfhydryl, and carboxylate groups have a special attraction to zinc ions. These ions are important for the angiotensin-converting enzyme (ACE) to work properly. So, drugs with these groups can stick to the ACE and block it.

The carboxylic acid group in the N-ring of ACE inhibitors is crucial for their activity. This group imitates a natural molecule, so it fits perfectly into the ACE and blocks it. Without this group, the drug loses its ability to stop ACE from working.

Compound (b) is the most potent ACE inhibitor because it has an extra hydrophobic group attached to the pyrrolidine ring. This makes it a better fit for the ACE's binding site.

Lisinopril can move through the digestive system and get into the bloodstream even though it's very water-loving (hydrophilic). This is because it has a specific charge that makes it easier to cross the membranes of the gut and get to the cells where it's needed.

The presence of two carboxylate groups and a secondary amine in Enalaprilat's structure makes it highly hydrophilic (water-loving) and less lipophilic (fat-loving).

Enalaprilat's low lipophilicity contributes to its poor absorption in the gut, leading to reduced oral bioavailability.

In the acidic environment of the stomach (pH 1.5), Enalaprilat's carboxylic acids are non-ionized, while its secondary amine becomes protonated, giving it a positive charge.

In the slightly basic environment of the small intestine (pH 7), both carboxylic acids and the secondary amine are ionized, resulting in two negative charges and one positive charge on Enalaprilat.

Esterification of a carboxylic acid group in Enalaprilat enhances its lipophilicity by replacing a hydrophilic group with a more lipophilic ester.

Esterification also reduces the pKa of the secondary amine, making it less basic and less likely to become positively charged in the intestine. This reduces its overall polarity.

By esterifying only one carboxylic acid, Enalaprilat can achieve a zwitterion form with a neutral overall charge at pH 7. This facilitates absorption across cell membranes.

The zwitterion form of the esterified Enalaprilat promotes better gastrointestinal absorption and bioavailability because it can more easily traverse biological membranes.

A type of lipid disorder characterized by an excess of cholesterol, cholesterol esters, triglycerides, and phospholipids in the blood plasma.

Lipoproteins are classified based on their density, which reflects the protein-to-lipid ratio. They are categorized as: Very-low-density lipoproteins (VLDLs), Intermediate-density lipoproteins (IDLs), Low-density lipoproteins (LDLs), and High-density lipoproteins (HDLs).

HMG-CoA reductase is the primary control enzyme in cholesterol biosynthesis. It converts 3-hydroxy-3-methylglutaryl (HMG)–CoA to mevalonic acid.

Bile acid sequestrants are highly positively charged molecules that bind to negatively charged bile acids in the intestine. This prevents bile acids from solubilizing lipids, thus blocking cholesterol absorption.

Mevastatin, Simvastatin, Atorvastatin.

The activity of HMG-CoA reductase inhibitors is sensitive to the lactone ring's stereochemistry, its ability to be hydrolyzed, and the length of the bridge connecting the two ring systems.

Pravastatin is more hydrophilic than simvastatin or lovastatin because it has a ring-opened dihydroxy acid with a 6-hydroxyl group. This increased hydrophilicity results in minimal penetration into peripheral cells, better selectivity for liver tissue, and potentially reduced side effects compared to other statins.

Ezetimib incorporates hydroxyl and p-fluoro groups. The hydroxyl enhances water solubility and localizes the compound in the intestines, while the p-fluoro groups inhibit undesirable metabolism.