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📚 Notes: Physicochemical Properties & Drug Action

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1. Introduction

• The biological response of a drug is elicited when it interacts with receptors (enzymes, cell membrane components, proteins, nucleic acids).
• Physicochemical properties and stereochemical features greatly affect drug-receptor interaction by influencing drug transport from site of administration to site of action.
• Key physicochemical properties: Solubility, Partition Coefficient, Acid-Base Properties, Chemical Bonding, Chelation, and Surface Activity.

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2. Solubility

• A drug must dissolve before it can pass through the gastrointestinal tract after oral administration.
• Dissolution depends on: chemical structure, particle size, crystal form, tablet coating, and tablet matrix.
• Biochemical reactions occur in an aqueous phase - so water solubility is a critical physical property.
• Polar nonionic compounds form hydrogen bonds with water via -OH, -NH, -SH, >C=O groups - these get hydrated.
• Nonpolar compounds interact with water through hydrophobic bonds and get dispersed.
• The equilibrium of drug between aqueous phase and lipid phase (fat-tissue depot) is a key determinant of drug action - this is where partition coefficient comes in.

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3. Partition Coefficient

• While water solubility gets the drug to the membrane surface, lipid solubility drives diffusion across the membrane.
• Rate of diffusion of a neutral molecule depends on:
  • Concentration gradient on either side of the membrane
  • Lipid/water partition coefficient (P) of the drug

P = [drug]lipid / [drug]water (equilibrium constant)

• Higher P → faster diffusion into the membrane.
• Measured experimentally using n-octanol / water system (n-octanol approximates the polar properties of the lipid bilayer; pH 7.4 phosphate buffer for aqueous phase).
• P is an additive property - each structural component contributes to lipophilicity or hydrophilicity.
• Other systems (hexane-water, chloroform-water) are poor models as they contain very little water in the organic phase.

• Shaking method (direct measurement in octanol/water)
• HPLC or TLC (chromatographic techniques)
• Calculation from atomic contributions (each atom has a fixed contribution to P)

• Explains mode of action of nonspecific general anaesthetics
• Explains action of barbiturates as hypnotics
• Explains disinfectant action on bacterial membranes

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4. Acid-Base Properties

• Many drugs are acids or bases; acid-base properties affect distribution and partitioning in a biological system.
• Bronsted-Lowry definitions:
  • Acid = proton donor
  • Base = proton acceptor
• Acid dissociation: HA + H₂O → H₃O⁺ + A⁻ (water acts as base)
• Base reaction: B + H₂O → BH⁺ + OH⁻ (water acts as acid)

• pKa = -log Ka
• Henderson-Hasselbalch equation:
  • pH = pKa + log [conjugate base] / [acid]
  • Used to calculate pH of weak acid/base solutions and buffers.
• For bases: pKa = pKb - 14 (basicity expressed as pKa of the protonated/conjugate acid form)

• Drugs in unionised (nonpolar) form cross lipid membranes of capillary walls and cell membranes more readily.
• Acidic drugs (pKa 4-5): partly nonionic in stomach (pH ~2) → partly absorbed in stomach; major absorption in intestine.
• Basic drugs (pKa 9-10): protonated in stomach → NOT absorbed there; absorbed in intestinal tract (pH ~8).

% Ionisation = 100 / (1 + 10^(pKa - pH))

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5. Chemical Bonding

5.1 Van der Waals Forces (London Dispersion Forces)

• Result of polarisability - asymmetry in electron cloud induced by a neighbouring nucleus.
• Operate within distance of 0.4 to 0.6 nm
• Bond energy: 0.3 to 1.9 kJ/mol
• Weakest interactions

5.2 Hydrophobic Interactions

• Occur in nonpolar/hydrocarbon structures that cannot form hydrogen bonds with water.
• Nonpolar groups → water becomes ordered (loss of entropy) around them.
• When two hydrophobic groups come together → ordered water displaced → entropy gain → free energy decreases by ~3.4 kJ/mol per methylene group.
• Role: stabilisation of protein conformations, drug-protein binding, binding of steroids to receptors.

5.3 Hydrogen Bonding

• Electrostatic interaction between nonbonding electron pair of a heteroatom (N, O, S) and an electron-deficient hydrogen of -OH, -NH, or -SH.
• Strongly directional - linear bonds preferred over angular bonds.
• Weak but important for stabilising structures (e.g., α-helix of proteins, base-pairing in nucleic acids).

5.4 Charge-Transfer Interactions

• Formed by transfer of charge from an electron-rich donor to an electron-deficient acceptor.
• Donors: π-electron systems, aromatic compounds with electron-donating groups, aromatic heterocycles, alcohols, ethers, thiols, amines.
• Acceptors: π-electron deficient systems (e.g., picric acid), purines, pyrimidines.
• Example: Iodine in cyclohexene → cyclohexene-iodine complex (brown colour) vs. iodine in cyclohexane (violet).
• Drug relevance: Chloroquine (antimalarial) and Actinomycin-D (antibiotic) intercalate with DNA via charge-transfer.

5.5 Dipole-Dipole and Ion-Dipole Interactions

• Arise from partial charge separation due to electronegativity differences between adjacent atoms.
• Dipole moment expressed in Debye units (vector sum of all bond moments).
• Evidence: Potency of procaine and local anaesthetic analogues directly related to the dipolar character of the ester carbonyl group.

5.6 Ionic Bonds

• Formed between ions of opposite charge (e.g., quaternary ammonium salts: R₄N⁺...I⁻).
• Very strong electrostatic attraction.
• Important in the action of ionisable drugs.

5.7 Covalent Bonds

• Formed by sharing of electrons between atoms.
• Strongest of all bonds.
• Most drugs combine with receptors via weak molecular interactions (collectively strong but individually reversible).
• Covalent drug-receptor interactions are generally irreversible - less common but important examples:
  • Heavy metal antiparasitic drugs (arsenic/antimony): covalent bond with sulphydryl (-SH) groups of parasite enzymes.
  • Nitrogen mustards (anti-neoplastic): alkylate guanine bases in DNA and cross-link DNA strands.
  • Penicillin: acylates transpeptidase enzyme (vital for bacterial cell wall synthesis).
  • Organophosphates: inhibit cholinesterases.

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6. Chelation

• Metal ion complexes formed from electron-donating molecules (ligands) and a metal ion with incomplete valency.
• Electron-donating atoms in a ligand molecule: N, O, S
• Ligands can be: di-, tri-, or polydentate (depending on number of electron-donating groups).
• Chelate = ring structure formed when a complexing agent binds a metal ion.
• Sequestration = chelating agents that confer water solubility (sequestering agents).
• EDTA (Ethylenediaminetetraacetic acid) = classic example of a complexing agent.

• Penicillamine (D-form, S configuration): Forms water-soluble chelate with copper → used in Wilson's disease (excess serum copper). Also used in long-term oral treatment of lead poisoning.
• Tetracyclines: Contain dimethylamino and enolic groups → form stable complexes with Ca²⁺, Mg²⁺, Al³⁺ → explains why absorption is delayed when co-administered with dairy products, aluminium hydroxide gels, or calcium/magnesium/iron/zinc salts.

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7. Surface Activity

• Many compounds act through surface phenomena: detergents, ion transport agents, disinfectants, antibiotics.
• Biomembranes are the largest surface area in living systems - essential to all cell function.
• Any agent disrupting the membrane of a microorganism can act as an anti-microbial agent.

• Aliphatic alcohols: bactericidal by damaging bacterial membranes → rapid loss of cytoplasmic constituents.
• Phenol and cresol: denature proteins of bacterial membranes.
• Adding an alkyl chain to phenol (e.g., hexylresorcinol) increases surface activity.
• Quaternary ammonium compounds (benzalkonium chloride, cetrimide, cetylpyridinium chloride): bactericidal via surface-active properties.
• Phenol (pKa 9.9) can penetrate the lipid layer of skin (unlike ephedrine hydrochloride) due to its ability to partition through the lipid layer.

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8. Stereochemical Features

Optical Isomerism

• Most common type of isomerism in medicinal chemistry.
• Results from molecular asymmetry (chiral centre).
• Three-point attachment hypothesis (L.H. Easson & E. Steadman, 1933): Stereochemical specificity occurs because one enantiomer achieves three-point attachment to a receptor while the other can only achieve two-point attachment.

• Labetalol: Diastereoisomeric mixture of 4 stereoisomers - (R,R)-isomer → β-blocking; (S,R)-isomer → α₁-blocking.
• D-Penicillamine (S): Antiarthritic; L-Penicillamine: extremely toxic.
• (S,S)-Ethambutol: Antitubercular; (R,R)-Ethambutol: has ocular toxicity.

• D-Asparagine: sweet; L-Asparagine: tasteless
• (R)-Carvone: caraway odour; (S)-Carvone: spearmint odour

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Geometric Isomerism

• Results from restricted rotation at C=C double bonds or rigid ring systems.
• Isomers have significantly different physical, chemical properties and distribution patterns in biological systems.
• Stilboestrol: Trans (E)-isomer is oestrogenic; cis (Z)-isomer is only 7% as active (trans-isomer has topographic resemblance to oestradiol).
• Tranylcypromine: (1R,2S)-(+)-isomer is more active MAO inhibitor; (-)-isomer is more effective blocker of amine uptake.

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Conformational Characteristics

• Conformations = different arrangements of atoms convertible into one another by rotation about single bonds.
• Conformers = conformational isomers.
• Preferred conformation of a drug molecule in relation to receptor binding is an important area of medicinal chemistry.

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Summary Table - Bond Strengths (Weakest to Strongest)

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