UNIT-1.pptx medical chemistry b pharmacy
- 2. INTRODUCTION • Branch of chemistry which is intersection of organic, pharmacology and other biological specialtites • It includes drug design, development and synthesis • Also encloses the discipline of drug synthesis and Structure Activity Relationship (SAR)
- 3. History • She nung (Chinese Emperor) made first pharmacopeia • The 13th -20th century chemical analysis techniques were developed • Natural products were used • Example: cocoa leaves for hallucination • Opium as painkiller • 19th century-age of innovation and chemistry
- 4. History • Morphine derivatives introduced as cough sedative in 1898 • 1840 first use of synthetic anathesia • 1864- bartuturic acid as hypnotic • 1875- salicyclic acid for typhoid fever • 1928- discovery of penicillin
- 5. Structure of Biological membrane • Cell membrane consist of phospholipid bilayer
- 6. Physicochemical properties in relation to biological action • The therapeutic effect is related to various physicochemical properties of the molecule • Physical property • Chemical property
- 7. Various physico- chemical properties • Solubility • Partition coefficient • Hydrogen bonding • Ionization • Redox potential • Complexation • Isosterism
- 8. Solubility • Concentration of dissolved solute, which is in equilibrium with the solid state • Solubility depends on nature of solute , temp, pH and pressure • Expressed In terms of affinity/philicity • Atoms are held together by different types of bonds • These forces are involved in solubility
- 9. Methods to improve solubility • Structural modification • Use of cosolvents • Employing surfactants • Complexation
- 10. Importance • Bioavailability of drugs • Drug must be in solution form before it interacts with receptors • Biochemical reactions are based on solubility • In each compartments, the degree of solubility vary
- 11. Factors • Ionization • Size and molecular structure • Stereochemistry • Electronic structure
- 12. Interaction of non-polar drugs • It is based on hydrophobic interactions • Example: 1. The LA activity of PABA is based on their lipid solubility 2. In homogenous series antibacterial activity changes with molecular weight 3. n-Butanol and n-Pentanol are active against S. aureus while higher members cannot reach due to lack of solubility in water
- 13. According to IP the solubility is indicated by
- 14. Application • For better absorption of drugs in GI fluid the aqueous solubility of the drug must be greater than 1% • Provides information about intermolecular forces of interaction , useful for finding drug receptor interactions • For purification • For transdermal and intramuscular drug delivery
- 15. Partition coefficient • Influence the drug transport and drug distribution • Defined as equilibrium constant of drug concentration for unionized molecule in two phases
- 16. Partition coefficient • For ionizable molecules (acids, bases, salts) the degree of ionization is denoted by alpha in aqueous solutions • Affects drug transfer characteristics • Functional group and structural arrangement help to determine the lipophilic and hydrophilic character of drug molecules • Used in QSAR
- 17. Factors affecting • pH • Co solvents • Surfactant • Complexation
- 18. Importance • Effect drug absorption and distribution • Predict distribution of drug • Drugs are designed with low logP to reduce toxicity and non-specific binding
- 19. Ionization • Accumulation of ionized drug in body compartment is known as ‘ion trapping’ • Depends on it pH and pKa • Used to derive effective partition coefficient • Example: Phenobarbital pKa is 7.4 i.e. it would be unionized in acidic environment
- 20. Importance • Lower the pH relative to the pKa greater is the fraction of protonated drug (charged or uncharged) • Weak acid at acidic pH: RCOO- + H+ RCOOH • Weak base at alkaline pH: RNH3 + RNH2 + H+
- 21. Hydrogen bond • Dipole-dipole interaction between hydrogens • In polar bonds such as N-H, O-H or F-H • Weak bonds • Molecules capable of H-bonding are soluble in water • Two types: 1. Intermolecular 2. Intramolecular
- 23. Intramolecular H-Bonding • Also known as chelation • Decreases the boiling point
- 24. H- bonding and biological activity
- 25. H- bonding and biological activity
- 26. Effect of H-bonding • Physical properties effected by H-bonding 1. Boiling and melting point 2. Water solubility 3. Strength of acids 4. Spectroscopic properties 5. Surface tension and viscosity 6. Drug-receptor interactions
- 27. Protein binding • Process in which drug molecules bind with proteins forming a complex or • Reversible binding of protein with non-specific and non-functional site on body without showing any biological effect
- 28. Protein binding • It is of two types: 1. Intracellular binding 2. Extracellular binding • Biological activity depends on affinity between drug and protein • Extensive binding may prolong the action • Highly bound drugs have longer duration of action and lower volume of distribution
- 29. Important factor for biological activity
- 30. • Protein binding values are given as
- 31. Complexation/Chelation • Complex or coordination compounds are result of donor-acceptor mechanism • Intramolecular forces can also be involved in the formation of complexes • Divided broadly into two categories depending on whether the acceptor compound is metal ion or an organic molecule
- 32. Applications • Example: 1. Dimercaprol is a chelating agent. It is an effective antidote for organic arsenical, Lewisite, but can also be used for treatment of poisoning due to antimony, gold and mercury. 2. Penicillamine is an effective antidote for the treatment of copper poisoning because it forms water-soluble product with copper and other metal ions.
- 33. Applications 3. 8-hydroxyquinoline and its analogs act as antibacterial and antifungal agents by complexing with iron or copper
- 34. Bio-isosterism • 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 • Classified into two types: 1. Classical bioisosterism 2. Non- classical bioisosterism
- 35. Classical Bioisosterism • They have similarities of shape and; • Electronic configuration of atoms, groups and molecule they replace • The classical bio isosters may be: A. Univalent atoms and groups: i. Cl, Br, I ii. CH3, NH2, -OH, -SH B, Bivalent atoms and groups iii. R-O-R, R-NH-R, R-S-R, RCH2R iv. -CONHR, -COOR, -COSR
- 36. Classical Bioisosters C. Trivalent atoms and groups D. Tetravalent atoms and groups =C,=N, =P= E. Rong equivalent
- 37. Applications • Replacement of –NH2 group by –CH3 group
- 38. Applications • Replacement of –OH and –SH • Guanine= -OH • 6-thioguanine= -SH
- 39. Non classical bioisosterism • Do not obey the steric and electronic definition of classical isosters • Functional groups with dissimilar valence electronic configuration • Specific characteristics are: • Electronic properties • Physicochemical property of atom/molecule • Spatial arrangement • Functional moiety for biological activity
- 40. • Examples: • Halogens Cl, Br, F, CN • Ether –S-. –O • Carbonyl group • -OH, -CH2OH, -NHSO2R
- 41. Stereochemistry • Plays a major role in pharmacological properties because: 1. Any change in stereo specificity will affect its pharmacological properties 2. Isomeric pairs have different physical properties thus differ in pharmacological activity
- 42. Conformational isomers • Different arrangement of atoms that can be converted into one another by rotation about a single bond are conformations • Example: acetylcholine
- 43. Optical isomers • Important for biological activity of the drugs • Because it is able to achieve three points of attachment with receptor • While its enantiomers would only be able to achieve two-point attachment
- 44. Optical isomers • Category of drugs where two isomers have similar pharmacological activity but different quantitative potencies
- 46. Drug metabolism • Metabolic changes of drug and related products • Process of converting drug into product or inert substances before reaching the site of action • Biotransformation: specific term for chemical transformation of xenobiotics in living organisms
- 47. • Liver is the primary site for mrtabolism • Several isoforms CYP450 (CYP) enzymes are involves
- 48. Phases of drug metabolism • Phase-I: • Converts parent drug to more polar metabolites by inserting polar functional groups • Such as: -OH, -COOH, -SH, -NH2 • Reactions involve functionalization reactions oxidation, reduction, hydrolysis • Also called non-synthetic phase • Produces hydrophilic compounds • Metabolite may be active or inactive
- 49. Phase-II • Synthetic phase • Involves conjugation reactions of functional groups or metabolites to form hydrophilic product • Reactions include: glucurinodation, glutathione conjugation, acetylation, methylation, sulfonation • Metabolite is inactive
- 50. Sites of metabolism • Liver • Plasms • GIT • Lungs • Skin • Nasal mucosa • Kidney
- 51. Sites of drug metabolism
- 53. Oxidation • Addition of oxygen/negatively charged radical • or removal of hydrogen or positively charged radical • Reactions carried out by group of monooxygenases in liver
- 54. Oxidation of alcohol • Aliphatic and aromatic alcohols undergo oxidation to form corresponding acids • Catalysed by alcohol dehydrogenase
- 55. Oxidation of aldehyde • Aldehydes undergo oxidation to form corresponding acids
- 56. Oxidation of olefins • Undergo oxidation to form epoxides • It may further undergo enzymatic hydration to form trans-1,2- dihydroxyoxides
- 57. Oxidation of aromatic ring • Undergo oxidation to form epoxide intermediate • Which rearranges to form arenol • Example: phenobarbital forms hydroxyphenobarbital
- 58. Oxidation of alpha carbon • Carbon adjacent to carbonyl group undergoes oxidation to form hydroxy derivatives
- 59. Sulphur oxidation • Sulphur is oxidized to form oxides of sulphur • Example: albendazole (anthelmintic drug) is oxidized in the presence of FMO
- 60. N-oxidation • Forms N-oxides • Voriconazole N-oxide also has weak antifungal properties • But also generates ROS • Potential skin cancer inducing subtances
- 61. Amine oxidation • Amines are oxidized to form carboxylic acids • High level of tyramine can cause hypertension crisis
- 62. Reduction • Large drug substances containing azo groups, aldehyde and nitro groups undergo reduction • 1. Reduction of aldehyde: • Undergo reduction by enzymes aldo-keto reductase • Example: chloral
- 63. Reduction of nitro compound • Undergo reduction to form corresponding aromatic amines • Example: nitrazepam metabolizes to its 7-amino metabolite
- 64. Reduction of disulphide • Reduction of compounds containing disulfide to inactive compounds • Example: reduction of disulfiram to N,N-diethyliocarbamic acid
- 65. Azo reduction • Yields primary amines • Example: activation of protonsil
- 66. Reductive dehalogenation • Replacement of halogen attached to carbon • Example: Halothane
- 67. Hydrolysis • Commonly with drugs containing ester and amide functional group 1. Hydrolysis of esters: • Example: Aspirin undergoes metabolism by hydrolysis to form salicyclic acid
- 68. Hydrolysis of amides • Hydrolyzed slowly as compared to esters
- 69. Phase-II metabolism • Conversion to more polar and soluble products • Attaches small polar and ionizable endogenous molecules such as glucuronic acid, sulfate, glycine and glutamine • Methylation and acylation generally do not increase water solubility • Resulting products are inactive
- 70. 1. Glucuronic acid conjugation • Most common metabolic reactions • Active form is UDP-Glucuronic acid
- 71. Glucuronic acid conjugation • Drugs like morphine, acetaminophen, chloramphenicol and propranolol undergo metabolism
- 72. 2. Sulphate conjugation • Common in drugs having hydroxy group, phenol and aromatic amines with sulphotransferase • Most common pathway in steroidal drugs undergo this reaction
- 73. 3. Acetylation • Involves conjugation with acetyl CoA using enzyme acetyl transferase • Drugs containing amino or hydrazine functional group undergoes acetylation • Example: acetylation of Isoniazid
- 74. 4. Glycine conjugation • Glycine is most common amino acid • Forms water soluble ionic conjugates with aromatic, aliphatic and heterocyclic carboxylic acid and their derivatives
- 75. 5. Methylation • Most endogenous amines undergo methylation • Enzyme: methyltransferase
- 76. 6. Glutathione conjugation • Important pathway for detoxification • Reactive against electrophilic compounds like epoxide, alkyl halides, sulphonates • These conjugates are converted to mercaptopuric acid and excreted in bile • Catalyzed by enzyme glutathione transferase
- 80. Enzyme induction • Phenomenon of increased drug metabolism ability of enzymes • Mechanism: • Increase in both liver size and liver blood. • Increase in both total and microsomal protein content. • Increased stability of the enzymes • Increased stability of cytochrome P-450. • Decreased degradation of cytochrome P-450 • Proliferation of smooth endoplasmic reticulum
- 81. • Example:
- 82. Enzyme inhibition • Decrease in drug metabolizing ability • Inhibition may be direct or indirect 1. Direct Inhibition: Result from interaction at enzymatic site Mechanism: Competitive inhibitors Non-competitive inhibitors Product inhibition
- 83. Enzyme inhibition • Indirect inhibition: caused by one of the following mechanisms: • Repressions: may be due to fail in rate of enzyme synthesis or increased rate of enzyme degradation • Altered physiology: due to nutritional deficiency or hormonal imbalance • Example:
- 84. Biological factor 1. Age: metabloc rate different in different age groups • In neonates ( up to 2 month) and in infant (2 months to 1 yr), the microsomalenzyme system is not fully developed, so drug metabolized slowly. Eg. Caffeine has half life of 4 days in neonates in comparison to 4 hrs in adult • Children (between 1 yr and 12 years)metabolize several drugs much more rapidly than adults as rate of metabolism reaches a maximum. • In elderly person, the liver size is reduced, the microsomal enzyme activity is decreased and hepatic blood flow also declines as a result of reduced output, all of which contributes to decreased metabolism drugs
- 85. 2. Diet • The enzyme content and activity is altered by number a number of dietary component. • Low protein diet decreases and high protein increases the drug metabolism. As enzyme synthesis is promoted by protein diet. • Free fat diet decrease cytochrome P-450 level since phospholipids, Which are important components of microsomes become deficient. • Grape fruit inhibits metabolism of many drugs and improve their oral bioavailability. • Starvation results in decreased amount of glucuronides formed than under normal conditions.
- 86. 3. Gender Difference • Different in males and females due to sex hormones • In human studies women metabolize benzodiazepines slowly than men
- 87. 4. Species difference • Difference observed in phase-I and Phase-Ii • Human liver contains less CYP450/gm of tissue than liver of other species • Example: rat liver contains 30-50nmol/g of CYP-45O whwreas human contains 10-20 nmol/g
- 88. 5. Strain difference • Different drug metabolizing activity are observed in different strains. • This can be studied as: 1. Pharmacogenetics: A study of inter-subject variability in drug response Polygenetic control is observed in twins Little or no difference in identical twins but large variation were observed in dizygotic twins
- 89. Strain difference • Ethnic variations: • Difference observed in metabolism of drug among different races • Such variations may be monomorphic or polymorphic • Example: approximately equal percent of slow and rapid acetylators are found among whites and black; whereas slow acetylators dominate Japenese and Eskimo population
- 90. 6. Altered physiological factors • Pregnancy • Disease states • Hormonal Imbalance • Circadian rhythm