Physicochemical properties in biological action .pdf

Factors affecting drug metabolism medicinal chemistry

1. Physicochemical
properties in relation to
biological action

2. Major physicochemical properties are;

Ionisation Solubility
Partition coefficient Hydrogen bonding
Protein binding Chelation
Bioisosterism Geometrical and optical
isomerism

3. Ionisation and Pka value
Drug ionisation depends on its Pka and pH.
Pka influences absorption and drug passage through cell membrane .
Drug Pka helps adjust pH to ensure maximum solubility in ionic or non
ionic form. eg.- Tropicamide eye drops( anticholinergic drug) with pKa- 5.2
has to be buffered to pH 4 to obtain more
than
90 percentage ionisation.
Drugs in ionised form distribute more than unionisedform in the body.
Drugs must cross lipid barriers with many ionic phospholipid, protein
species, that can repel or bind ionic drugs to reach receptor site of action,
therefore ,the unionised form of drug easily pass through membranes .
Non ionised form turns ionised and activated at Pka in the range 6 to 8

4. High degree of ionisation prevent drug absorption from GI tract , decreasing
systemic toxicity ex.,- antibacterial sulfanilamide remain in git and fight
infection.
PH change affect acidic and basic groups on cell surface or within the cell
.At isoelectric point the cation in protein zwitterion gives higher biological
action at increasing pH and anion at decreasing pH.

5. Solubility
Solubility and water permeability are
important factors. , for drug interactions with
cellular structure. and to reach target sites
drugs require aqueous and lipid solubility.
Solubility is expressed in terms of affinity or
repulsivity to polar or nonpolar solvents

6. Intermolecular forces affecting solubility
●Vanderwaals
●Dipole -dipole
●Ion-dipole
●Ionic bonding



Methods to improve water
solubility
●Salt formation
●Watersolubiliser groups
incorporation
●Use special dosage
forms

7. Rate and extend of dissolution is the major factor controlling drug absorption.
●Sparingly water soluble drugs deposit on the route to site of action , causing clogging
up and organ damage
Ex .,- sulphonamide crystallization in kidney.
●Poor solubility is also sometimes helpful
1.Ex.,- penicillin G procaine is converted to salt form to act as a slow releasing
penicillin.
2.Unacceptable bitter taste of chlorpromazine .HCl is masked by converting to water
insoluble embonate salt.
●Hydrolysis by water helps in metabolism of drugs with hydrolysable functional groups
like ester or amine
Ex ,- local anaesthetic Lignocaine on hydrolysis gives 2,6 dimethyl amine as metabolite
●Lipid solubility ( alkyl chain length)is proportional to local anaesthetic activity
Ex.- in a series of p- amino benzoic acid.

8. Partition coefficient
Defined as the equilibrium constant of drug concentration for a molecule in lipid and aqueous
phases.
Methods to measure partition coefficient log P as the
measure of lipophilicity are
●Shake flask method with a measured amount
of 7.4 pH buffer or water - n octanol mixture.
●Chromatography using RPHPLC
●Computational method using hydrophobic
fragmentation constant of the molecule.

Ratio of unionised drug distributed between
aqueous and lipid phase at equilibrium
Partition coefficient=drug(lipid
Importance of partition coefficient
●Predicting drug distribution in biological
system
●Determine drug bioavailability in drug design
, By Lapibski rule of 5 compounds with logP
less than 5 - good bioavailability.

9. Hydrogen Bonding
Types
●Intermolecular
Hydrogen Bonding
●Intramolecular
Hydrogen Bonding
1.Hydrogen bonding in
biological action
2.Solvent property of water
3.Enzyme and antibodies 3D
structure
4.Antigen antibody binding.

10. Application of Hydrogen Bonding

●Hydrogen bonding in 1 phenyl 3
methyl 5 pyrazolone (
Antipyrine)is inactive
-Analgesic.
●Salicylic acid - antibacterial
propertiy P and m isomers of
salicylic acid are inactive ,
Because salicylic acid forms
intramolecular Hydrogen Bonding so
it's less water soluble and it's
partition coefficient is also greater..

M and p

11. Protein binding
Reversible binding on nonspecific and non-functional site on body protein without any biological effect is
called. Protein binding
Drug+ protein = drug- protein complex
Drug protein complex is large hence cannot pass through phospholipid bilayers like capillary membranes,
glomerular membranes in nephron, blood brain barriers,to prolong the duration of action
Higher degree of protein binding ,- higher half-life, smaller volumes of distribution,as bound fraction is not
available for action ( acts as temporary storage to drug)
Acidic drugs generally bind to plasma albumin and basic drugs to alpha 1 acid glycoprotein
Neutral and basic with lipoproteins
Bound drugs escape first pass metabolism.

12. Factors affecting protein binding
●Higher lipid content of drug moiety= Higher rate of protein binding.ex - IM of cloxacillin show 95% protein
binding.
●Change in drug and protein concentration.
●Drug affinity for protein/ tissue.ex-digoxin more affinity for cardiac muscle than skeletal muscles.
CHELATION /COMPLEXATION
●Donor- acceptor mechanism/ Lewis acid base reaction
●Complex drug can't pass through natural membranes, therefore reduce the drug absorption rate
●Compounds obtained by donating electrons to metal ion with ring structure formation called chelates.
●Donor atom or ion is called ligand.
Importance of chelates in medicine
1.Dimercaprol chelating agent - effective antidote for gold and arsenic poisoning
2.Watersoluble ligands( sequestering agent) ex - EDTA - remove metals causing deterioration of epinephrine and
ascorbic acid.
3.Chelation of antihypertensive hydralazine with iron remove it
4.8Hydroxy quinoline and analogs CTS as antibacterial and antifungal agents on complexing with iron or copper.

13. BIOISOSTERISM
Bioisosteres
Classified into classical and non classical.
Groups or compounds that possess near equal molecular shape and volume
approximately the same distribution of electrons and similar physical properties.
Drug design by isosteric modification involve replacement of atoms or group of
atoms in a molecule by another group with similar electronic and steric
configuration .