Question

Which of the following statement is INCORRECT about antianginal organic nitrates?

• A. Ester prodrugs of nitric acid and polyols
• B. Release nitric oxide to show therapeutic effect
• C. Alkyl Nitrates with hydrocarbon chains
• D. Lipophilic compounds and rapidly absorbed through bio-membranes

Hint:

To easily differentiate functional groups: - Nitro compounds: \( \text{R-NO}_2 \) (Carbon directly bonded to Nitrogen). - Nitrate esters (the antianginal drugs): \( \text{R-O-NO}_2 \) (Carbon bonded to Oxygen, which is bonded to Nitrogen).

Answer 1

The Correct Option is C

Concept: Organic nitrates are the oldest and most frequently used class of drugs for the acute relief of angina pectoris (chest pain caused by reduced blood flow to the heart). Prominent examples include Nitroglycerin (glyceryl trinitrate), Isosorbide dinitrate, and Isosorbide mononitrate. We need to evaluate the chemical nature and pharmacokinetics of these compounds to find the false statement.

Step 1: Evaluate Option (A): Ester prodrugs of nitric acid and polyols.
This statement is perfectly true. Chemically, drugs like nitroglycerin are synthesized by the esterification of polyols (alcohols containing multiple hydroxyl groups, like glycerol) with nitric acid (\(\text{HNO}_3\)). They are referred to as nitrate esters (\(\text{R-O-NO}_2\)). They act as prodrugs because they must be biologically transformed in the body to release their active form.

Step 2: Evaluate Option (B): Release nitric oxide to show therapeutic effect.
This statement is undeniably true. It is the core mechanism of action of this drug class. Once inside the vascular smooth muscle cells, organic nitrates undergo enzymatic degradation (often involving mitochondrial aldehyde dehydrogenase) to release free Nitric Oxide (NO). NO activates guanylyl cyclase, increasing cGMP levels, which leads to the dephosphorylation of myosin light chains and profound vasodilation, relieving the angina.

Step 3: Evaluate Option (C): Alkyl Nitrates with hydrocarbon chains.
This statement is INCORRECT. Organic nitrates used therapeutically are nitrate esters of specific polyhydric alcohols (polyols), not simple alkyl nitrates with long straight hydrocarbon chains. An alkyl nitrate would simply be an alkane chain attached to a nitrate group (e.g., ethyl nitrate, propyl nitrate). Such simple straight-chain alkyl nitrates are highly volatile, highly explosive, and generally too toxic or possess inappropriate pharmacokinetic profiles for standard antianginal therapy. The drugs used are complex esters of cyclic or highly branched polyols (like isosorbide).

Step 4: Evaluate Option (D): Lipophilic compounds and rapidly absorbed through bio-membranes.
This statement is true. Drugs like nitroglycerin are highly uncharged and highly lipophilic (fat-soluble). Because of this profound lipid solubility, they cross biological membranes extremely rapidly. This is precisely why nitroglycerin is so effective when administered sublingually (under the tongue); it absorbs rapidly through the oral mucosa directly into the systemic circulation, providing relief within minutes while bypassing first-pass liver metabolism. Conclusion: Because antianginal organic nitrates are polyol nitrate esters and not simple straight-chain hydrocarbon alkyl nitrates, Option (C) is the completely incorrect statement.