JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B. Pharmacy II Year MEDICINAL CHEMISTRY-I Previous Question Paper (August/September - 2022 - R17)

The biological activity of a drug molecule is fundamentally determined by its physicochemical properties, which dictate its ability to reach the target site, interact with the receptor, and undergo metabolism and excretion. The key properties are as follows:

1. Solubility and Partition Coefficient (Log P): Solubility is essential for drug absorption. The partition coefficient, defined as the ratio of drug concentration in octanol to water, measures lipophilicity. A balanced Log P is required; high lipophilicity may lead to poor aqueous solubility and sequestration in fat tissues, while low lipophilicity prevents the drug from crossing biological membranes via passive diffusion.

2. Ionization (pKa): Most drugs are weak acids or bases. The degree of ionization at physiological pH is governed by the Henderson-Hasselbalch equation:

Only the unionized form of a drug can readily permeate lipid membranes. Therefore, the pKa of a drug determines its absorption profile in different regions of the gastrointestinal tract.

3. Hydrogen Bonding: Hydrogen bonds are critical for the binding affinity of a drug to its target (e.g., enzymes or receptors). They influence both the solubility of the drug in the aqueous environment and the specificity of the drug-receptor interaction.

4. Stereochemistry: Biological receptors are chiral. Optical isomers (enantiomers) often exhibit different pharmacological activities. One enantiomer may be highly potent, while the other may be inactive or even toxic, as seen in the case of thalidomide.

5. Molecular Size and Shape: The molecular weight and spatial arrangement of functional groups determine whether a drug can fit into the binding pocket of a target macromolecule. The 'Rule of Five' suggests that poor absorption is likely if the molecular weight exceeds 500 Daltons.

6. Electronic Effects: The distribution of electrons within a molecule, influenced by inductive and resonance effects, affects the acidity, basicity, and reactivity of the drug. These properties influence how the drug interacts with the target through electrostatic forces or covalent bonding.

7. Protein Binding: Drugs bind to plasma proteins like albumin. This interaction acts as a reservoir, regulating the concentration of the free, active drug in the bloodstream. High protein binding can prolong the duration of action but may also lead to drug-drug interactions.

Drug metabolism, primarily occurring in the liver, is influenced by several physiological, pathological, and chemical factors:

• Physiological factors: Age significantly affects metabolism; neonates have immature enzyme systems, while elderly patients often show reduced metabolic capacity. Gender differences exist due to hormonal influences on cytochrome P450 enzymes.
• Pathological factors: Liver diseases such as cirrhosis, hepatitis, or obstructive jaundice directly impair the functional capacity of hepatocytes, leading to decreased metabolism.
• Genetic factors: Genetic polymorphism leads to variations in enzyme expression, resulting in 'fast' or 'slow' metabolizers for specific drugs.
• Chemical factors: Enzyme induction (e.g., by phenobarbital) increases the rate of metabolism, while enzyme inhibition (e.g., by ketoconazole) decreases it, potentially leading to drug toxicity.
• Dietary factors: Nutritional status, such as protein deficiency, can reduce the synthesis of metabolic enzymes.

Phase-I reactions, also known as functionalization reactions, introduce or expose a polar functional group (like -OH, -NH2, -SH, or -COOH) on the drug molecule, making it slightly more hydrophilic and providing a handle for Phase-II conjugation. The primary reactions include:

1. Oxidation: The most common reaction, catalyzed by the microsomal cytochrome P450 monooxygenase system. It involves the addition of oxygen or removal of hydrogen. Examples include aromatic hydroxylation, N-dealkylation, O-dealkylation, and S-oxidation.
2. Reduction: Occurs less frequently than oxidation and is typically catalyzed by reductases. It involves the addition of hydrogen or removal of oxygen, commonly affecting azo, nitro, and carbonyl groups.
3. Hydrolysis: Catalyzed by esterases and amidases in the plasma, liver, and other tissues. It involves the cleavage of drug molecules by the addition of water, typically affecting esters and amides to yield alcohols and acids or amines.