PHYSICO CHEMICAL PROPERTIES IN RELATION TO BIOLOGICAL ACTIVITY

DEFINITION: The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with. 1)Physical Properties Physical property of drug is responsible for its action 2)Chemical Properties The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.

Various Physico-Chemical Properties are, üSolubility üPartition Coefficient üIonization üHydrogen Bonding üChelation üSurface activity üIsosterism

ROUTES OF ADMINISTRATION The choice of appropriate route in a given situation depends upon both drug as well as patient related factors. Drugs administered locally or systematically. The drugs administered through systemic routes is intended to be absorbed into blood & distributed all over.

Different Routes Of Drug Administrations Oral/ Swallowed Oral/ Sublingual Rectal Epithelial Inhalation Parentral Topical: local effect, substance is applied directly where its action is desired. v Epicutaneous (application onto the skin), e. g. allergy testing, typical local anesthesia v Inhalational, e. g. asthma medications v Enema, e. g. contrast media for imaging of the bowel v Eye drops (onto the conjunctiva), e. g. antibiotics for conjunctivitis v Ear drops - such as antibiotics and corticosteroids for otitis externa

ABSORPTION: The process by which the drug is released in the body from its dosage form is known as absorption. Drug absorption is the movement of a drug into the bloodstream. The factors which effect the rate of absorption are ◦ Concentration of the drug ◦ Route of administration ◦ Solubility of the drug ◦ Dissolution rate for solid dosage form

◦ Blood circulation to the site of application and the area of the absorbing surface in local applications. ◦ Physico-chemical parameters of the drug. To reach he site of action the drug has to cross one or more membrane barriers. The main process by which a drug molecule cross the neutral barrier is, ◦ Simple diffusion ◦ Facilitated diffusion ◦ Pore transport ◦ Diffusion of the ion across the membrane ◦ Active transport ◦ phagocytosis 7

DISTRIBUTION: Once the drug has been absorbed into the blood , it distributed around the body. It get distributed throughout the blood supply , with in a minute. As the blood recirculates, the drug moves from the bloodstream into the body's tissues. Drug is evenly distributed through out the blood supply, this does not mean the drug is evenly distributed around the body. Since he blood supply is rich in some areas of the body than the other. 8

Drugs penetrate different tissues at different speeds, depending on the drug's ability to cross membranes. For example, the anesthetic thiopental, a highly fat-soluble drug, rapidly enters the brain, but the antibiotic penicillin, a water-soluble drug, does not. In general, fatsoluble drugs can cross cell membranes more quickly than water-soluble drugs can. Distribution of a given drug may also vary from person to person. For instance, obese people may store large amounts of fat-soluble drugs, whereas very thin people may store relatively little. Older people, even when thin, may store large amounts of fat-soluble drugs because the proportion of body fat increases with aging. 9

METABOLISM: Drug metabolism is the chemical alteration of a drug by the body. metabolism is what the body does to the drug, Some drugs are chemically altered by the body (metabolized). The substances that result from metabolism (metabolites) may be inactive, or they may be similar to or different from the original drug in therapeutic activity or toxicity. Some drugs, called prodrugs, are administered in an inactive form, which is metabolized into an active form. 10

The resulting metabolites produce the desired therapeutic effects. Metabolites may be metabolized further instead of being excreted from the body. The subsequent metabolites are then excreted. The termination of the drug effect is caused by bio transformation and excretion. all the substance in the circulatory system , including drugs , metabolites , and nutrients will pass through the liver. A significant portion of the drug metabolised by hepatic enzyme to inactive chemical. 11

Storage sites Plasma proteins, certain tissues, neutral fat, bone and transcelluar fluids(gastro intestinal tract)are found to act as a drug reservoirs or storage sites for drugs. Plasma proteins: approximately 6. 5% of the blood constitute the proteins, of which 50% I albumin. The drug can also be stored in the tissue depots. Neutral fat constitutes some 20%o 50% of body weight and constitutes a depot of considerable importance. 12

The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots. The ultra short acting, lipophilic barbiturate thiopental’s concentration rapidly decreases below its effective concentration following administration. It disappears into tissue protein, redistributes into body fat, and then slowly diffuses back out of the tissue depots but in concentrations too low for a pharmacological response. In general, structural changes in the barbiturate series that favours partitioning into the lipid tissue stores decrease duration of action but increase central nervous system depression. Conversely, the barbiturates with the slowest onset of action and longest duration of action contain the more polar side chains. 13

PROTEIN BINDING: The reversible binding of protein with non-specific and non- functional site on the body protein with out showing any biological effect is called as protein binding. Protein + drug ⇌ Protein-drug complex Depending on the whether the drug is a weak or strong acid , base or is neutral. It can bind to single blood proteins to multiple proteins. The most significant protein involved in the binding of drug is albumin, which comprises more than half of blood volume. 14

protein binding values are normally given as the percentage of total plasma concentration of drug that is bound to all plasma protein. 15

NEUTRAL FAT: Since fat constituents around 10%(starvation) to 50% of the total body weight. it serves as a main storage site for drugs having a high partition coefficient(lipid/water system) or a high lipid solubility(thiobarbiturates). 16

Drug Receptor Interactions RECEPTOR A macromolecular component of the organism that binds the drug and initiates its effect. Traditional model was a rigid “Lock and Key” – Lock Receptor surface – Key Drug or Ligand

TYPES OF RECEPTORS Four Primary Receptor Families (i)Ligand-gated ion channels (ii) G-protein (Guanine nucleotide-regulatory protein) coupled receptors. iii) Tyrosine Kinase-linked Receptors (iv) Intracellular receptors regulating gene transcription

Covalent interactions Ionic interactions Drug Receptor Interactions Hydrogen bonding interactions Vander Waals interactions Hydrophobic interactions

Solubility: • The solubility of a substance at a given temperature is defined as the concentration of the dissolved solute, which is in equillibrium with the solid solute. • Sufficient solubility and membrane permeability is an important factor for oral absorption. • The measurement of aqueous solubility depends upon the following facts. , 1) Buffer & Ionic strength 2) Polymorphism & Purity of the sample 3) p. H 4) Super saturation 5) Thermodynamic Vs Kinetic solubility

In ascending homologous series, the Physico chemical properties like boiling point, viscosity, surface activity and partition coefficient increases then the aqueous solubility decreases. The solubility characteristics of a drug can be increased or decreased by derivatisation. Eg: Methyl predinisolone acetate(water insoluble) is changed to Methyl predinisolone Sodium succinate(water soluble). Eg: Convertion of chloramphenicol(slightly soluble) to chloramphenicol Palmitate (insoluble)

Methods to improve solubility of drugs 1) 2) 3) 4) Structural modification Use of co solvents Employing surfactants Complexation

Partition Co-efficient Partition co-efficient is one of the Physico chemical parameter which influencing the drug transport & drug distribution. , the way in which the drug reaches the site of action from the site of application. Partition co-efficient is defined as equilibrium constant of drug concentration for a molecule in two phases. P[Unionized molecule] = [drug]lipid [drug]water P[Ionized molecule] = [drug]lipid [1 -a ][drug]water a=degree of ionization in aqueous solution.

Factors affecting Partition Co-efficient Ø p. H Ø Cosolvents Ø Surfactant Ø Complexation Partition Co-efficient are difficult to measure in living system. They are usually determined in vitro 1 -octanol as a lipid phase and phosphate buffer of p. H 7. 4 as the aqueous phase.

• The Partition co-efficient, P is dimensionless and its logarithm, log P is widely used as the measure of lipophilicity. • The log P is measured by the following methods. 1) Shake flask method 2) Chromatographic method 3) Spectroscopy method • Phenobarbitone has a high lipid/water partition coefficient of 5. 9. Thiopentone sodium has a chloroform/water partition coefficient of about 100, so it is highly soluble in lipid.

Surface Activity: surfactant is defined as a material that can reduce the surface tention of water at low concentration. Surface active agents affect the drug absorption which depends on: 1. The chemical nature of surfactant 2. Its concentration 3. Its affect on biological membrane and the miscelle formation.

§ At lower concentration the surfactant enhances the absorption rate, the same in higher concentration reduce the absorption rate. Applications: 1. The antihelmentic activity of hexylresorcinol 2. Bactericidal activity of cationic quaternary ammonium compounds. 3. Bactericidal activity of aliphatic alcohols. 4. Disinfectant action of phenol and cresol.

Hydrogen Bond The hydrogen bond is a special dipole-dipole interaction between non bonding electron pairs of hetero atoms like N, S, O and electron deficient hydrogen atom in polar bonds such as OH, NH, F etc. These are weak bonds and denoted as dotted lines. O-H……. O, HN-H……. O, • The compounds that are capable, of forming hydrogen bonding is only soluble in water.

Hydrogen bonding is classified in 2 types. 1) Intermolecular hydrogen bonding

2) Intramolecular Hydrogen bonding salicylic acid o-nitrophenol

Hydrogen Bonding and biological action Eg. 1) Antipyrin i. e. 1 - phenyl 2, 3 - dimethyl 5 - pyrazolone has analgesic activity. 1 -phenyl-3 -methyl-5 -pyrazolone is inactive.

Salicylic acid(O-Hydroxy Benzoic acid has antebacterial activity para and meta Hydroxy Benzoic acids are inactive.

CHELATION DEFINITON: The compounds that are obtained by donating electrons to a metal Ion with the formation of a ring structure are called chelates. LIGANDS: The compounds capable of forming a ring structure with a metal are termed as ligands.

Importance of chelates in medicine: a)Antidote for metal poisoning 1. Dimercaprol is a chelating agent. 2. Penicillamine 1: 1 chelate 1: 2 chelate

b)8 -Hydroxyquinoline and its analogs acts as antibacterial and anti fungal agent by complexing with iron or copper. C) Undesirable side effects caused by drugs, which chelates with metals. A side effect of Hydralazine a antihypertensive agent is formation of anemia and this is due to chelation of the drug with iron.

Redox Potential: The oxidation-reduction potential may be defined as a quantitative expression of the tendency that a compound has to give or receive electrons. The redox potential of a system may be calculated from the following equation. E=E 0+0. 0592/n log[conc. of reductant /conc. of oxidant] Examples of interfering with natural redox system in biological conditions: 1) Riboflavin analogues The biological activity of riboflavin is due to E =-0. 185 volt.

Examples, 1) Riboflavin analogues The biological activity of riboflavin is due to E =-0. 185 volt. Riboflavin E 0 = -0. 185 V Riboflavin analogue E 0 = -0. 095 V 2). The optimum bacteriostatic activity in quinones is associated with the redox potential at +0. 03 volt, when tested against Staphylococcus aureus.

Ionisation and Pka Most of the drugs are either weak acids or base and can exist in either ionised or unionised state. The ionisation of the drug depends on its p. Ka & p. H. The rate of drug absorption is directly proportional to the concentration of the drug at absorbable form but not the concentration of the drug at the absorption site. Eg: Aspirin in stomach will get readily absorbed because it is the un-ionosed form(99%). Eg; Barbituric acid is inactive because it is strong acid. 5, 5 disubstituted Barbituric acid has CNS depressant action because it is weak acid. in

Acids are two types-Unionized acid - HA Ionized acid - BH + According to Henderson-Hasselbalch equation PH = pka+log[Un ionised form][ionised form % ionisation = 100( 1+10 (p. H-pka) )

By using drug p. Ka, the formulation can be adusted to p. H to ensure maximum solubility in water or maximum solubility in non-polar solvent. The PH of a substance can be adjusted to maintain water solubility and complete ionisation.

Eg: Phenytoin injection must be adjusted to Ph 12 with Sodium Hydroxide to obtain 99. 98% of the drug in ionised form. Tropicamide eye drops, an anti cholinergic drug has a pka of 5. 2 and the drug has to be buffered to Ph 4 to obtain more than 90% ionisation.

STERIC FEATURES OF DRUGS ØThe drug most possess a high degree of structural specificity or stereo selectivity. ØMany drugs show stereo selectivity because mostly reeptor binds are optically active biological macromolecules such as protein, polynuclootide or glycolipds. For e. g. Diethyl stilbosterol

Conformational Isomers Different arrangement of atoms that can be converted into one another by rotation about single bonds are called conformations. Rotation about bonds allows inter conversion of conformers.

A classical example is of acetylcholine which can exist in different conformations. Staggered 2 -Acetoxycyclo propyl trimethyl ammonium iodide

Optical Isomers Stereochemistry, enantiomers, symmetry and chirality are impotant concept in therapeutic and toxic effect of drug. A chiral compound containing one asymmetric centre has two enantiomers. Although each enantiomer has identical chemical & physical properties, they may have different physiological activity like interaction with receptor, metabolism & protein binding. A optical isomers in biological action is due to one isomer being able to achieve a three point attachment with its receptor molecule while its enantiomer would only be able to achieve a two point attachment with the same molecule.

(-)-Adrenaline (+)-Adrenaline

E. g. Ephedrine & Psuedoephedrine

The category of drugs where the two isomers have qualitatively similar pharmacological activity but have different quantitative potencies.

Geometric Isomerism Geometric isomerism is represented by cis/trans isomerism resulting from restricted rotation due to carbon double bond or in rigid ring system.

ISOSTERISM Longmuir introduced the term isosterism in 1919, which postulated that two molecules or molecular fragments containing an identical number and arrangament of electron should have similar properties and termed as isosteres. Isosteres should be isoelectric i. e. they should possess same total charge.

Bioisosterism is defined as compounds or groups that possess near or equal molecular shapes and volumes, approximately the same distribution of electron and which exhibit similar physical properties. They are classified into two types. , i)Classical biososteres ii)Non classical bioisosters.

Classical Bioisosteres They have similarities of shape and electronic configuration of atoms, groups and molecules which they replace. The classical bioisosteres may be, Univalent atoms and groups i)cl, Br, I ii) CH 3 NH 2, -OH, -SH Bivalent atoms and groups i) R-OR, RNH-R, RSe. R ii) –CONHR, -COOR, -COSR

Trivalent atoms and groups i)-CH=, -N= ii) –p=, -AS= Tetravalent atoms and groups =c=, =N=, =P=

Application of Classical Bioisosteres in in drug design i) Replacement of –NH 2 group by –CH 3 group. Carbutamide R= NH 2 Tolbutamide R= CH 3 ii)Replacement of –OH & -SH Guanine= -OH 6 -Thioguanine = -SH

Non classical Bioisosteres Ø They do not obey the stearic and electronic definition of classical isosteres. Ø These isosteres retain activity by the retention of their properties such as p. Ka, electrostatic potentials, which can alter selective enzyme processes.

Examples Halogens cl, F, Br, CN Ether -S-, -O Carbonyl group Hydroxyl group –OH, -NHSO 2 R, CH 2 OH Catechol

A classical e. g. of ring Vs. noncycclic structure is Diethylstilbosterol & 17 -ß oestradiol.

REFERENCES: 1. Thomas L. LEMKE , David A. WILLIAMS , Victoria F. ROCHE, S. William ZITO, Foye’s Principles of Medicinal Chemistry , Wolters kluwer Pvt. Ltd, New Delhi , 6 th Edition , Pg. no. 210 – 298. 2. William A. Remers, Jaimes N. Delgado, Wilson& Grissvold’s Text book of organic, Medicinal and pharmaceutical Chemistry , 10 th. Edition , Pg. no. 3 -10 59

3. Donald. J. Abraham , BURGER’S Medicinal chemistry Drug Discovery , Wiley inter science publication , 6 th Edition , Volume -2, Pg. no. 649 – 653. 4. Rama rao Nadendla , Principles of organic Medicinal Chemistry , New age International Pvt. Limited Publishers , Pg. no. 14 - 28. 5. www. wikipedia. com 60

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