PHYSICOCHEMCAL PROPERTIES IN RELATION TO DRUG ACTION.pptx

Physicochemical properties in relation to drug action

1. Physicochemical properties in relation to drug action Submitted by: Shazia Bashir M.Pharm First year ( MPC) Submitted to: Dr. Mohd Akbar Dar

2. DRUG : Chemical substance that is administered to incite a biological effect in the body of an organism. DRUG ACTION : The action of a drug is believed to be due to interaction of that drug with endogenous or exogenous substrate molecules found in the body. This interaction causes change or inhibit the biological activity of these molecules. The effectiveness of a drug in bringing about these changes normally depends on the stability of the drug-substrate complex. Drug + Receptor = Drug-Receptor complex Pharmacological response

3. Physicochemical properties of the drug molecule that may have an effect on its biological activity are given as : IONISATION SOLUBILITY PARTITION COEFFICIENT HYDROGEN BONDING PROTEIN BINDING BIOISOSTERISM OPTICAL AND GEOMETRICAL ISOMERISM

4. IONIZATION Ionization refers to the process of conversion of unionized molecule to ionized molecule by gain or loss of electron. Most of the drugs are either weak acids or base and can exist in either ionized or unionized state. Ionization = protonation or deprotonation resulting in charged molecules.

5. Ionization affecting drug activity : >Ionization plays important role in pharmacokinetics(ADME) of a drug. For best absorption and distribution of drug there should be good balance between ionized and unionized form of drug. >More the unionized drug more will be its absorption and less will be the solubility. >Mostly acidic drugs are less ionized in stomach hence more absorbed at gastric acidic pH. >Basic drugs are mostly absorbed at alkaline pH in intestines due to their less ionization.

6. For calculating the percentage drug existing in ionized or unionized form at given pH: The degree of dissociation or ionization can be determined by HENDERSON HASSILBALCH EQUATION : For weak acids pH = pKa + log ionized unionized For weak bases pOH = pKb + log unionized ionized

7. SOLUBILITY The solubility of a substance is defined as the maximum amount of solute that can be dissolved in 100ml of solvent at a given temperature. Solubility of a drug may be expressed in terms of its affinity/repulsion for either polar or nonpolar solvent. The relative solubilities of drugs in aqueous media and lipid tissues of the body play a major role in their absorption and transport to their sites of action. To pass through a membrane a drug must usually exhibit a reasonable degree of both water and lipid solubility. The appropriate degree of water solubility will often improve drug distribution in circulatory system as well as drug action.

8. SOLUBILITIES SOLUBILITIES VALUE(part of solvent required per part of solute) very soluble less than 1 part freely soluble 1- 10 Parts soluble 10-30 parts sparingly soluble 30-100 parts slightly soluble 100-1000 parts very slightly soluble 1000-10000 parts practically insoluble greater than 10000 parts

9. Methods to improve solubility of drugs 1.Structural modification(alter the structure of molecule). 2. Use of co-solvents (Ethanol, sorbitol, PEG). 3. Employing surfactants. 4. Complexation. Importance of solubility 1.Bioavailibility of drugs mainly depends on their solubility in the given solvent system. 2.Solubility is important as it governs the preparation of liquid dosage form and the drug must be in solution form before it is absorbed by the body to produce the biological effect. 3. Drug must be in solution form to interact with receptors.

10. Partition Coefficient The ratio of concentration of a compound(drug) in the two immiscible phases. The measure of differential solubility of the compound between these two solvents. P = conc of drug in organic solvent conc of drug in aqueous solution Drug (aq) Drug (lipid) polar phase nonpolar phase

11. Partition coefficient Useful in estimating the distribution of drugs within the body. Hydrophobic drugs with high partition coefficients are preferentially distributed to hydrophobic compartments such as lipid bilayers of the cells. While hydrophilic drugs( low partition coefficients) preferentially are found in hydrophilic compartments such as blood serum. Partition coefficient, P is dimensionless and its logarithm, log P is widely used as the measurement of lipophilicity. 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 lipid soluble. Hence, thiopentone sodium is used as ultra-short acting barbiturate.

12. Hydrogen bonding The hydrogen bonding is a special type of dipole-dipole interaction between the hydrogen atom in a polar bond such as N-H,O-H or F-H and electronegative atom O,N and F. Dipole results from unequal sharing of electrons between atoms within a covalent bond. The compound that are capable of forming hydrogen bond is only soluble in water. Hydrogen bonding is classified into two types: Intermolecular Intramolecular

13. Intermolecular hydrogen bonding It occurs between two or more than two molecules of the same or different compound. Due to this bonding boiling point of molecule increases, it is due to increase in molecular weight of molecule increases, hence more energy is required to dissociate molecule for vaporization.

14. 2. Intramolecular hydrogen bonding It occurs within two atoms of the same molecule or compound. This type of hydrogen bonding is also known as chelation as it leads to the formation of chelates. Due to this bonding boiling point of molecule decreases. Examples :

15. Importance of hydrogen bonding Hydrogen bonding stabilizes 3d structure of drug targets, such as proteins and RNA. It is also an important determinant of binding affinity of drugs for their targets and anti-targets. Hydrogen bonding increases the strength and stability of a drug receptor interaction substantially.

16. Protein binding Most drugs posses physicochemical affinity for plasma proteins and get reversibly bound to these. Acidic drugs generally bind to plasma albumin and basic drugs to α 1acid glycoprotein. Binding with albumin is more important.

17. Drugs highly bound to plasma protein s.no To albumin To α 1-acid glycoprotein 1 Barbiturates Β -blockers 2 Benzodiazepines Bupivacaine 3 NSAIDs Lidocaine 4 Phenytoin Imipramine 5 Penicillin's Methadone 6 Tetracycline's Quinidine 7 Sulphonamides Prazosin

18. Importance Protein binding can have a profound effect on the drug’s effective solubility, bio-distribution, half-life in the body and interaction with other drugs. Protein binding also can prolong the drug’s duration of action. Protein binding phenomenon can lead to some clinically significant drug-drug interactions resulting when one drug displaces another from the binding site on albumin. Bound drugs are less available to enzymes involved in first pass metabolism. Drug with high protein binding activity values tend to have a greater half-life compared to those with lower values.

19. Bioisosterism Bioisosteres are compounds or groups that have same physical and chemical properties, approximately the same distribution of electrons producing broadly similar biological effects. Replacement or modification of functional group with other group having similar properties is known as isosteric or bioisosteric replacement. Procainamide, an amide, has a longer duration of action than procaine an ester, because of the isosteric replacement of the ester oxygen with a nitrogen atom. They are classified into two types: i ) classical bio- isosteres ii) Non classical bio- isosteres

20. 1. Classical bioisosteres They have similarities in shape and electronic configuration which they replace. The classical bio- isosteres may be

21. 2. Non classical bio- isosteres

22. Optical and Geometrical isomerism Optical isomers are compounds that contain at least one chiral carbon atom or compounds that differ only in their ability to rotate the polarized light. The isomer which rotates light to the right(clockwise): dextrorotatory(+). The isomer which rotates light to the left (anti-clockwise): levorotatory(+). Optical isomers can have large differences in potency, receptor fit, biological activity, transport and metabolism. For example: levo-phenol has narcotic, analgesic and antitussive properties, whereas its mirror image, dextro-phenol has only antitussive activity.

23. Geometrical Isomerism Geometrical isomerism is represented by cis/trans isomerism resulting from restricted rotation due to carbon-carbon double bond or in rigid ring system. They are not mirror images and have different physicochemical properties. For example, cis-diethylstilbestrol has only 7% of the oestrogenic activity of trans-diethylstilbestrol.

24. References Alagarsamy, V., 2013. Textbook of Medicinal Chemistry Vol I-E-Book (Vol. 1). Elsevier Health Sciences. Block, J. and JM, B., 2003. Wilson and Gisvold’s Organic Medicinal and Pharmaceutical Chemistry. Thomas, G., 2004. Fundamentals of medicinal chemistry. John Wiley & Sons. Kar, A., 2005. Medicinal chemistry. New Age International.