1. Medicinal Chemistry - Lecture 5 PHYSICOCHEMICAL PROPERTIES OF DRUG MOLECULES Joseph O. Oweta | PHC 2204

2. Surface Activity Effects of Drug Molecules The capacity to cross biological membranes and barriers is important for most drugs. However, there are also pharmaceutical agents that display mechanisms of action that are more dependent upon activities at surfaces. Pharmacologic reactions may occur on biological surfaces and interfaces. The energy situation at a surface differs markedly from that in a solution because special intermolecular forces are at work; Therefore, surface reactions require specific consideration.

3. Surface Activity Effects of Drug Molecules In living organisms, membranes comprise the largest surface, covering all cells (the plasma membrane) and many cell organelles (the nucleus, mitochondria, and so forth). Dissolved macromolecules such as proteins also account for an enormous surface area (e.g., 1ml of human blood serum has a protein surface area of 100m 2 ).

4. Functions of Biological Membranes (i)serve as a scaffold that holds a large variety of enzymes in proper orientation, (ii)provide and maintain a sequential order of enzymes that permits great efficiency in multistep reactions, and (i)serve as the boundaries of cells and many tissue compartments. (ii)In addition, many drug receptors are bound to membranes.

5. Surface Activity Effects of Drug Molecules It is therefore apparent why the physical chemistry of surfaces and the structure and activity of surface-active agents are also of interest to the medicinal chemist. Antimicrobial detergents and many disinfectants exert their activity by interacting with biological surfaces and are important examples of surface-active drug effects.

6. Surface Interaction and Detergents Origin of Surface Tension All molecules in a liquid phase interact with each other and exert a force on neighbouring molecules. The hydrogen-bonding interaction of water molecules that creates clusters. The water molecules at a gas–liquid interface, however, are exposed to unequal forces, and are attracted to the bulk water of the liquid phase because no attraction is exerted on them from the direction of the gas phase. This accounts for the surface tension of liquids.

7. Surface Interaction and Detergents Principle of Dissolution Because the dissolution of a solid is the result of molecular interaction between a solvent and the solid (which, once dissolved, becomes a solute), polar compounds capable of forming hydrogen bonds are water soluble, whereas nonpolar compounds dissolve only in organic solvents as the result of van der Waals and hydrophobic bonds.

8. Surface Interaction and Detergents Ampiphillic Compounds Compounds containing hydrophobic as well as hydrophilic groups will concentrate at surfaces and thereby influence the surface properties of these interfaces. Eg. Soap (Below)

9. Surface Interaction and Detergents Ampiphillic Compounds – Importance Bacteriocidal activity of quartenary ammonium compunds like cetrimide, Benzalkonium Chloride, etc Steroidal hormones and barbiturates have surface activity properties. Phenol and cresol act as disinfectants by denaturing proteins of biological membranes. Foaming agents, emulsifiers and surfactants.

10. Ionisation of Drugs The accumulation of an ionized drug in a compartment of the body is known as”ion trapping”. The ionization of a drug is dependent on its pKa and the pH. The pKa is the negative Logarithm of Ka. The Ka is the acidity constant of a compound, its tendency to release a proton.

11. Ionisation of Drugs Henderson- Hasselbalch relationship The ratio of ionized/ non ionized drug may be determined by the Henderson- Hasselbalch relationship.

12. Ionisation of Drugs Henderson- Hasselbalch relationship This may be used to derive an Effective partition coefficient : Ex: Phenobarbital pKa is 7.4. It is evident that phenobarbital would be predominantly in the unionised form in acidic environment.

13. Importance of ionisation of drugs 1.The lower the pH relative to the pKa greater is the fraction of protonated drug (protonated drug may be charged or uncharged) 2.weak acid at acidic pH : more lipid-soluble, becauses it is uncharged— the uncharged form more readily passes through biological membranes. Note that a weak acid at acidic pH will pick up a proton and become uncharged 3.Weak base at alkaline pH : more lipid-soluble, because it is uncharged— the uncharged form more readily passes through biological membranes. Note that a weak base at more alkaline pH will lose a proton, becoming uncharged RNH3

14. Drug Shape The shape of the drug is an important factor in defining the nature of the drug-receptor interaction. The three-dimensional shape of the drug is thought to interact with a complementary structural binding region of the receptor, typically a protein. The specific nature of the interaction defines whether the drug acts as an agonist promoting a change in cellular function or as an antagonist, which blocks the receptor usually resulting in no direct biological effect.

15. Drug Shape For example, consider acetylcholine or a synthetic analogue bethanechol (Urecholine). Interaction of these molecules with receptor (nicotinic or muscarinic cholinergic receptor) causes a physiological response i.e a decrease in heart rate for instance. In contrast, a muscarinic antagonist such as atropine may bind even more tightly than acetylcholine to muscarinic receptor but causes no direct effect. However, following administration of antagonist a biological response may be observed as a result of receptor blockade.