Physicochemical properties in relation to biological activity

1. Physicochemical properties in relation to biological activity • Drug distribution • A drug is a chemical molecule, following introduction into the body must pass through many barriers before it reach the site of action. • At the receptor the following equilibrium usually holds: • Drug + receptor → Drug – receptor complex (response)

2. Drug distribution

3. The ideal drug show favorable binding to the receptor and at the same time the drug dissociate from the receptor and reenter systemic circulation to be excreted. Oral administration of drugs is complex with respects to the physicochemical condition at the site of absorption. Therefore it is necessary to review GIT physiology. When a drug molecule moves from stomach into duodenum, the drug encounter a rapidly changing environment with respect to pH from 1-3 to 7-8. Furthermore, digestive juice secreted in intestine contains many enzymes not found in gastric juices. Drug absorption from the GIT or other sites; require the passage of the drug in non ionized form across the membrane barrier. The drug particle must first dissolve and if it possesses the desirable biopharmaceutical properties it will pass across the membrane into the blood. Most weak acid drugs are predominantly in the unionized form at lower pH of the gastric fluids , therefore absorbed from stomach.

4. GIT physiology

5. Biologic membrane • GIT membrane consists of a bimolecular lipoid layer in which protein are suspended .each phospholipids molecule of the lipoid bilayer is composed of a polar head (hydrophilic) locating at the surface of the membrane and two long non polar (hydrophobic)fatty acid tails.

6. Mechanisms of drug absorption 1. Passive diffusion The transfer of most drugs across biologic membrane occur by passive diffusion( a natural tendency for molecules to move from higher concentration to the lower one). Absorption by passive diffusion is first order. where absorption rate is directly proportional to the concentration at the site of absorption ; dc/dt α C .

7. 2. Active transport (carrier mediated) • For drugs of structural similarities to the substrate or normal cellular metabolites normally transported across the membrane. Active absorption is usually explained by assuming that carriers in membrane are responsible for shuttling these solutes in mucosal direction. • The number of apparent carrier in membrane is limited so that constant proportion of solute molecule presented to membrane is transported. Further increase in solute concentration will not lead to any further increase in the rate of absorption. • The capacity limited characteristic shows that the use of large single dose is irrational, and divided doses are preferable ,e.g., amino acid, 5 fluorouracil, methyldopa and penicillamine.

8. 3. Convective absorption • The absorption of small molecules with molecular radii less than about 4 angstroms through water filled pores of biologic membrane is referred as convective absorption. The rate of such absorption is equated to: • A-The relative size of the pores and the molecules • B-The rate of fluid or water absorptionb- • C-The concentration of the solute in the luminal content. • 4. Ion pair absorption • Highly ionized compounds such as quaternary ammonium compounds may be absorbed by ion pair mechanism.

9. The pH-partition hypothesis theory • Most drugs are absorbed from GIT by a passive diffusion of unionized moiety across a lipid membrane. Furthermore, the dissociation constant, pH of the fluid at the absorption site and lipid solubility determine the extent of drug absorption from solution. The interrelationship among theses parameters is known as the pH-partition theory. • Ionization and pH at absorption site • The fraction of the drug existing in unionized form in solution is a function of both dissociation constant and pH of the solution at absorption site. • The dissociation constant for both weak acid and weak bases is often expressed as pka (- log ka).

10. The Henderson –Hasselbach equation for ionization of weak acid • Weak acid HA + H2O (base)------------- A- + H3O+ • BH+ + H2O------- B(conj. Base) + H3O+ (conj acid) • Protonated amine(acid) • Ka = [H3O+][A-]/ [HA] Log ka = log[H3O+] +log[A-] –log[HA] • Where pH= - log[H3O+], pka = - log ka • pH = pka +log [A-]/ [HA] for HA acid • pH = pka + log [B]/[BH+] for BH+ acid • for weak base • B (base)+ H2O (acid) --------- BH+(conj. Acid) + OH-(conj. Base) • pH= pka + log [BH+]/[B] • pka + pkb = pkw = 14 • the pka and pkb values provide a convenient means of comparing the strength of weak acid and bases.

11. Problem • What is the ratio of ephedrine to ephedrine HCl (pka 9.6) in the intestinal tract at pH 8 • Answer • BH --------------- B + H+ • pH = pka + log [B]/[BH+] for BH+ acid • 8 =9.6 + log ephedrine /[ephedrine HCl] • log[ephedrine] /[ephedrine HCl]=-1.6 • the no whose log -1.6 = 0.025 this mean there are 25 part of ephedrine for every 1000 part of ephedrine HCl.

12. A plot of % ionization versus pH is illustrative of how the degree of ionization can be shifted with small change in pH. The curves for an HA acid (indomethacine) and BH (ephedrine HCl) are shown in the figure and from it we can note that: • When pH = pka the compounds are 50% ionized. • An increase 1 pH unit from the pka (increase in alkalinity ) results in HA acid become 90.9% ionized • Form and decrease in decrease of BH acid ionization to 9.1%. • An increase of 2 pH unit shift HA acid to complete ionization 99% and BH acid to nonionic conjugate base 0.99%. • Just the opposite is seen when the medium is made more acidic relative to the drugs pka value.

13. A plot of % ionization versus pH

14. Percentage of ionization • It is possible to calculate the % ionization of drugs using the following equation: • % ionization= 100/1+10(pka-pH) for HA acid • % ionization= 100/1+10(pH-pka) for BH+ acid • Lipid solubility • Some drugs may be poorly absorbed after oral administration even though they are available predominantly in unionized form in the GIT due to the low lipid solubility. • Drugs partition themselves between the aqueous phase and lipophilic membrane according to partition coefficient. the greater the value of partition coefficient the higher the lipid solubility of the solute.

15. Although drugs with greater lipophilicity are better absorbed ,it is imperative that drugs exhibit some degree of aqueous solubility ,because the availability of drug molecule in solution form is a prerequisite for drug absorption ,and the biologic fluids at the site of absorption are aqueous in nature. • The drugs must exhibit a balance between hydrophilicity and lipophilicity. • Drug passage from aqueous extra cellular fluid through lipid membrane to aqueous environment before reach the receptor.

16. Receptors • Receptors are integral proteins polypeptide macromolecules) that are embedded in the phospholipids bilayer of cell membrane. • Drug-receptor interaction • In order to appreciate mechanisms of drug action ,it is important to understand the forces of interaction that bind drugs to their receptor. • Forces involved in the drug-receptor interaction. • theForces involved in the drug-receptor complex are the same forces experienced by all interacting organic molecules. • In general the bonds formed between a drug and receptor are weak non covalent • Interactions, consequently the effects produced are reversible. Because of this, a drug because becomes inactive as soon as its concentration in the extra cellular fluids decreases. • For chemotherapeutic agents which act selectively on a foreign organism or for alkylating antineoplastic, an irreversible complex with the receptor through a covalent bond is desirable.

17. 1. Covalent bonds (electron sharing) • It is the strongest bond; it is seldom formed by a drug-receptor interaction except with enzyme and DNA. • 2. Ionic interactions (electrostatic) • For protein receptor at physiologic pH, basic groups of the amino acids side chain of argentine or lysine are protonated, while acid chain as in aspartic acid or glutamic acid ,the carboxylate deprotonated and give anionic group. • Drug and receptor group of opposite charge will be attracted, e.g. acetylcholine can undergo ionic interaction.

18. 3. ion- dipole and dipole- dipole interactions • As result of greater electro negativity of atoms such as O,S,N and halogen relative to C , C-X will have asymmetric distribution of electron ,this produce electronic dipoles. • The dipoles in a drug molecule can attracted by ions (ion-dipole interaction) or by other dipoles(dipole- dipole interactions) in the receptor . • 4. Hydrogen bonds • hydrogen bonds are a type of dipole- dipole interaction formed between the proton of a group X-H , where, X is an electronegative atom ,and other atom containing a pair of non bonding electron.

19. 5. Charge transfer complexes • When a molecule or a group that is a good electron donor comes into contact with a molecule or group that is a good electron acceptor, the donor may transfer some of its charge to the acceptor .this form charge transfer complex, which is a molecular dipole- dipole interaction. • 6. Hydrophobic interaction • When two non planer lipophilic groups on a drug and a receptor, each surrounded by ordered water molecules, approach each other, these water molecules become disordered in an attempt to associate with each other, this results in decrease in the free energy that stabilizes the drug receptor complex. This stabilization is known as a hydrophobic interaction. • 7. Van der Waals forces • As atoms from different molecules (drug& receptor) approach each other ,the temporary dipole of one molecule induce opposite dipoles in the approaching molecule ,consequently an intermolecular attraction known as van der waals forces will result. • Drug

20. Drug –receptor theory • The occupancy theory: • States that, the intensity of the pharmacological effect is directly proportional to the number of receptor occupied by the drug. The response ceases when the drug-receptor complex dissociate. However, not all agonists produce a maximal response; the occupancy theory is modified to account for partial agonists. • The modified occupancy theory: • The drug receptor interaction involve two stages • First there is a complex action of the drug with the receptor, termed affinity • sec., initiation of the biological effect which termed the intrinsic activity or efficacy. • In general, antagonists bind tightly to a receptor (great affinity ) but devoid of activity (no efficacy). this theory not explain why two drug that can occupy the same receptor can act differentially ;namely agonist and antagonist.

21. The rate theory • The rate theory suggests that the pharmacological activity is a function of the rate of association and dissociation of the drug with the receptor ,and not the number of occupied receptors .each association would produce a quantum of stimulus . • In the case of agonist the rate of association And dissociation would be fast ,while In the case of antagonist the rate of association would be fast but the dissociation would be slow. • This supported by the brief stimulation before blocking action of antagonist. • Partial agonists would have intermediate drug-receptor

22. The induced fit theory • According to this theory, an agonist would induce a conformational change in the receptor, this change responsible for the initiation of the biological effect. • The receptor was suggested to be elastic, and it could return to its original conformation after the drug was released. the drug also could undergo deformation.

23. Structural features and pharmacological activity • 1. Optical and geometric isomerism and pharmacological activity • 2. Conformational isomerism and pharmacological activity • 3. Isosterism and pharmacological activity • Optical isomers are differ only in their ability to rotate the plane of polarized light dextro or levo • Enantiomers are optical isomer mirror image have the same physical and chemical properties, their difference in biological activity must be due to stereochemistry; their ability to react selectively at an asymmetric center in biologic system. the following figure explain the difference in activity at asymmetric center; interaction of optical isomers of epinephrine at the proposed receptor site

24. interaction of optical isomers of epinephrine at the proposed receptor site

25. Geometric isomerism (cis &trans isomerism) • Indicate a type of diasteriomer that occur as a result of restricted rotation around a bond; C=C or C-C bond in ring system. • Diasteriomer have different physical properties one isomer may be highly ionized at physiologic pH resulting in difference in absorption and significant difference in biological activity. Unlike enantiomer ,it is difficult to correlate the difference in biological activity solely with difference in stereochemistry. • The observed difference in biological activity of Geometric isomer may be due in part to differences in the interatomic distances of the groups essential for activity.; • The interatomic distances between the OH group in Trans diethylstilbestrol and estradiol are similar, this explain why Trans isomer is 14 time estrogenic activity of the cis.

26. conformational isomerism is defined as non identical spatial arrangement of atom in a molecule, resulting from rotation about one or more single bond; Staggered, skew, fully eclipsed, partially eclipsed .chair or twist axial or equatorial substitution for maximal potency.

27. Isosterism • Chemical Isosterismaccording Longmuir; similarities in physicochemical properties of atoms, group, and molecules with similar electronic structure. E.g.N2 &CO, N2O& CO2 • According Erlenmeyer ; the electron in outer most shell of atoms are identical or almost identical., F ,Cl, Br ,I . • Hydride displacement law by Grimm; addition of small atom H and its lone electron to another atom results in pseudo atom .each vertical column represent a group of isosters. • N O F • CH NH OH • CH2 NH2 • CH3

28. Bioisosterism • Applied in drug design and molecular modification for creation of new and improved drugs. • Bioisosters are compounds which fit the broadest definition of isosters and have the same biological activity, even antagonistic. • Classical bioisosters: • Monovalent atoms and groups; e.g. –XHn where X is C ,N, O ,and S • Ring equivalent; interchange of -CH=CH- ,-S-, -O-, -NH-, -CH2-. • Non Classical bioisosters: • Exchangeable group • Cyclic ring versus non cyclic.