JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B.Pharmacy II MEDICINAL CHEMISTRY-I Previous Question Paper (August - 2021 - R17)

Physicochemical properties are fundamental factors that determine the pharmacokinetic and pharmacodynamic profile of a drug. These properties dictate how a molecule interacts with biological systems, including its absorption, distribution, metabolism, and excretion (ADME), as well as its affinity for target receptors.

Key properties include:

• Solubility: Drugs must possess an optimal balance of hydrophilicity and lipophilicity. High water solubility is required for dissolution in gastrointestinal fluids, while sufficient lipophilicity is necessary for crossing lipid-rich cell membranes.
• Partition Coefficient (Log P): This measures the lipophilicity of a drug. It is a critical determinant of membrane permeability. An optimal Log P value ensures the drug can traverse biological barriers effectively.
• Ionization (pKa): Most drugs are weak acids or bases. The degree of ionization at physiological pH (determined by the Henderson-Hasselbalch equation) influences the drug's ability to permeate membranes, as only the unionized form typically crosses lipid bilayers.
• Hydrogen Bonding: The capacity to form hydrogen bonds influences both solubility and binding affinity. Excessive hydrogen bonding can hinder membrane permeability, while specific hydrogen bond interactions are often essential for drug-receptor binding.
• Stereochemistry: The spatial arrangement of atoms significantly impacts biological activity. Enantiomers can exhibit different pharmacological effects, potencies, or metabolic pathways due to the chiral nature of biological receptors and enzymes.

Protein Binding: Many drugs bind to plasma proteins, primarily albumin (for acidic drugs) and alpha-1-acid glycoprotein (for basic drugs). This binding is usually reversible and involves weak forces like van der Waals interactions, hydrogen bonding, and ionic bonds. Protein binding acts as a reservoir for the drug, maintaining a steady concentration of free (active) drug in the blood. Only the unbound fraction is pharmacologically active and capable of crossing membranes or being metabolized/excreted. High protein binding can lead to drug-drug interactions, where one drug displaces another, potentially causing toxicity.

Chelation: Chelation involves the formation of a stable, ring-like complex between a ligand (the drug) and a metal ion (such as Fe2+, Ca2+, Mg2+, or Zn2+). This process can either enhance or inhibit biological activity. In some cases, chelation is the mechanism of action, such as in the use of EDTA to treat heavy metal poisoning by sequestering toxic ions. Conversely, chelation can reduce the bioavailability of drugs; for example, tetracycline antibiotics form insoluble chelates with calcium or magnesium ions found in dairy products or antacids, significantly reducing their absorption in the gastrointestinal tract.