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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)
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.
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.
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 absorptionbC-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.
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).
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.
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.
Percentage of ionization It is possible to calculate the % ionization of drugs using the following equation: % ionization= 100/1+10(pka-pH) % ionization= 100/1+10(pH-pka) for HA acid 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.
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.
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. the Forces 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.
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.
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.
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
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.
Isosterism
Chemical Isosterism according 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
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.