Factors affecting bioactivity (Beneficial or adverse effects of a drug on living matter.)

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Factors affecting bioactivity (Beneficial or adverse effects of a drug on living matter.)

Partition coefficient - Equilibrium constant of drug concentration for unionised molecule in two phases.

Eg. Phenobarbitone has a high lipid/water Partition coefficient whereas Thiopentone sodium has value about 100 and it is highly lipid soluble therefore used as ultra-short acting barbiturates.

Affected by factors such as

Complexation

Surfactants

Cosolvents

pH

Ionisation and pH - Protonation or deprotonation resulting in charged molecules.

Eg. Phenytoin injection must be adjusted to pH 12 with sodium hydroxide to obtain 99.8% of the drug in ionised form.

Unionised form helps the drug to cross the cell membrane.

Ionization form imparts good water solubility to the drug which is required to binding of drug and receptor interaction.

The rate of drug absorption is directly proportional to the conc of the drug at absorbable form.

Spatial consideration - Any change in stereospecificity will affect its activity

Geometric isomers - Physical properties of both the enantiomers are different. Eg. Cisplatin is a effective anti-cancer drug whereas Transplatin is not effective at all.

Optical isomers - Physical properties of both the enantiomers are identical. Eg. (R)-(+)-Thalidomide is a sedative whereas (S)-(-)-Thalidomide is a teratogen.

Hydrogen bonding - dipole-dipole interaction between H atoms in a polar bond.

Eg. 1-phenyl 2,3- dimethyl 5- pyrazolone has analgesic activity and 1-phenyl- 3- methyl-5- pyrazolone is inactive.

Intramolecular H bonding - occurs between two atom of the same molecules.

Intermolecular H bonding - occurs between two or more molecules of same or different compound.

Solubility- Drug must be in solution form before it is absorbed in the body to produce biological activity.

Methods to improve solubility

Complexations

Employing surfactants

Use of cosolvents (Ethanol, Sorbitol)

Structural modifications

Factors affecting solubility

pH, Nature of solvent, Pressure, Common ion effect etc

Temperature - As temperature increases, solubility increases

Boiling and melting point - As MP/BP increases, solubility decreases

Particle size - As size decreases, solubility increases

Resonance - A way of describing a molecule having delocalized set of electrons which cannot be expressed by a single structure.

Eg. Penicillin V has better bioavailability than Penicillin G as the ether oxygen on Penicillin V can be electron donating via resonance which is absent in Penicillin G.

Drug having resonance will have its bioactivity being reduced or increased by another functional group.

Inductive effect - Ability to either donate or withdraw electron from adjacent atom or functional group.

Eg. Penicillin V is superior to Penicillin G because it has electron withdrawing effect that allows Penicillium V to have better bioavailability.

Lipophilicity - Affinity of a drug for a Lipid environment.

Eg. CYP450 metabolism - Metabolic rate increases with increased Lipophilicity.

It is the result of intermolecular forces present in a solute and the two phases it partitions

Its measured as Partition coefficient or Distribution coefficient.

Bioisosterism - Compounds or groups that posses similar physical properties.

Non Classical bioisosteres - Functional group with dissimilar electronic configuration.

Eg. Ring VS Noncyclic structure of Diethylstilbestrol and 17-beta oectradiol.

Hydroxil group

Carbonil group

Ether

Catechol

Halogen

Classical bioisosteres - Similarities of shape and electronic configuration of atoms with which they are replaced.

Eg. Replacement of -NH2 in Carbutamide to -CH3 in Tolbutamide

Ring equivalent atoms/groups

Tetravalent atoms/groups such as =C=, =N= etc

Trivalents atoms/groups such as -P=, -N=

Bivalent atoms/groups such as R-O-R, R-S-R etc

Univalent atoms/groups such as Cl, Br, I etc

Redox potential - Tendency that a compound has to give or recieve electrons.

Eg. Riboflavin, ε0 = -0.185 V shows its effect on living matter whereas Dichlororiboflavin, ε0 = -0.095 V cannot be used as a drug.