ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)

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ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)

  1. 1. Refresher Course on Organic Chemistry and Organic Medicinal Chemistry Mr. Jan Dominique R. Lapig, RPh. April – May 2014
  2. 2. Part I: General Chemistry
  3. 3. The Study of Chemistry What is Chemistry? Chemistry is the study of the properties and behavior of matter. Science of the composition of matter and changes in composition it may undergo either spontaneously or because of intentionally established environmental condition. Matter – anything that occupies space and has mass.
  4. 4. Role of Chemistry in Modern Life • Biological molecules • Biochemical processes (cell  whole organism) • Medicines (Inorganic and Organic, Natural and semi-synthetic) eg: Aspirin • Drug discovery and development (Physicochemical properties, ADME)
  5. 5. Classification of Matter The basic difference between these states is the distance between the “bodies.” Gas – bodies are far apart and in rapid motion. Liquid – bodies closer together, but still able to move past each other. Solid – bodies are closer still and are now held in place in a definite arrangement.
  6. 6. Classification of Matter
  7. 7. Pure Substances and Mixtures Mixture – combination of two or more substances in which each substance retains its own chemical identity. – Homogeneous mixture – composition of this mixture is consistent throughout. • Solution: example syrup – Heterogeneous mixture – composition of this mixture varies throughout the mixture. Classification of Matter
  8. 8. Separation of Mixtures Mixtures can be separated by physical means. –Filtration –Chromatography –Distillation Classification of Matter
  9. 9. Separation of Mixtures Classification of Matter
  10. 10. Pure Substances and Mixtures It is also possible for a homogeneous substance to be composed of a single substance – pure substance. • Element – A substance that can not be separated into simpler substances by chemical means. • Atom – the smallest unit of an element that retains a substances chemical activity. Classification of Matter
  11. 11. Elements  There are ____ elements known.  Each element is given a unique chemical symbol (one or two letters). –C, N, Hg, Au, Mn –Notice that the two letter symbols are always capital letter then lower case letter because: CO – carbon and oxygen Co – element cobalt Classification of Matter
  12. 12. Compound: a substance composed of two or more elements united chemically in definite proportions.  The proportions of elements in compounds are the same irrespective of how the compound was formed.  Law of Constant Composition (or Law of Definite Proportions): “The composition of a pure compound is always the same, regardless of its source.” Classification of Matter
  13. 13. Properties of Matter Physical and Chemical Property Physical Property – a property that can be measured without changing the identity of the substance. Example: melting point, boiling point, color, odor, density Chemical Property: those that determine how a substance can be converted to another substance.
  14. 14. Physical and Chemical Property  Intensive properties – independent of sample size. Like temperature, refractive index, density, hardness.  Extensive properties – depends on the quantity of the sample (sample size). Like mass and volume Properties of Matter
  15. 15. Physical and Chemical Changes Physical change: the change in the physical properties of a substance. –Physical appearance changes, but the substances identity does not. –Water (ice)  Water (liquid) Properties of Matter
  16. 16. Physical and Chemical Changes Chemical change: (chemical reaction) – the transformation of a substance into a chemically different substance. – When pure hydrogen and pure oxygen react completely, they form pure water. – 2H2 + O2  2H2O Properties of Matter
  17. 17. Physical and Chemical Changes Properties of Matter
  18. 18. Physical Properties of Drug Molecule • Physical States: –Amorphous solid –Crystalline solid –Hygroscopic solid –Liquid –Gas
  19. 19. Physical Properties of Drug Molecule • Melting point: temperature at which a solid becomes a liquid. • Importance of melting point? – Water (0°C, 100°C) – Eutectic mixture –Packing: property of a solid; is a property that determines how well the individual molecules in a solid fit together in a crystal lattice
  20. 20. Physical Properties of Drug Molecule • Boiling point: temperature at which the vapor pressure of the liquid is equal to the atmospheric pressure
  21. 21. Physical Properties of Drug Molecule • Polarity: is a physical property of a compound, which relates other physical properties, e.g. melting and boiling points, solubility and intermolecular interactions between molecules –Bond polarity: is used to describe the sharing of electrons between atoms.
  22. 22. Physical Properties of Drug Molecule • Solubility: is the amount of a solute that can be dissolved in a specific solvent under given conditions. –Solute –Solvent –Solvation/hydration
  23. 23. Physical Properties of Drug Molecule • Unsaturated solution • Saturated solution • Supersaturated solution • Other definition of solubility: the maximum equilibrium amount of solute that can usually dissolve per amount of solvent
  24. 24. Physical Properties of Drug Molecule • Rate of Solution: is a measure of how fast a solute dissolves in a solvent. Depends on some properties like particle size, stirring, temperature and concentration
  25. 25. Acid-base properties and pH
  26. 26. Acid-base properties and pH • Arrhenius acids and bases –Acid: a substance that produces hydronium ion –Base: a substance that produces hydroxide ion –Neutralization reaction • Brönsted-Lowry acids and bases –Acid: proton donor –Base: proton acceptor
  27. 27. Acid-base properties and pH • Lewis acid: employ an electron lone pair from another molecule in completing the stable group of one of its own atoms. aka aprotic acid • Lewis base: any species that donates a pair of electrons to a Lewis acid to form a Lewis adduct. For example, OH− and NH3 are Lewis bases, because they can donate a lone pair of electrons.
  28. 28. pH and pKa values • pH: is defined as the negative of the logarithm to base 10 of the concentration of the hydrogen ion. The acidity or basicity of a substance is defined most typically by the pH value. • What is the pH of water? Blood plasma? Stomach?
  29. 29. pH and pKa values • pH - widely used method of expressing the hydrogen ion concentration of dilute acids, bases & neutral solutions in terms of pH. • pH is a mathematical definition of H+ that involves a numerical scale that runs from 0 - 14. It is the negative logarithm of the hydrogen ion. pH = 1 or pH = - log [H+] log [H+]
  30. 30. Sample Problem • The H+ concentration of an unknown liquid is 1 x 10-7 mole/L at 25°C. • What is the formula to be use? • Show the complete solution. • What is the pH of the unknown? • What is the unknown substance?
  31. 31. pOH • Although rarely used, the hydrogen ion (OH) concentration can be expressed as pOH, which is the negative logarithm of the hydroxide ion concentration or: pOH = 1 or pOH = - log [OH-] log [OH-]
  32. 32. Sample Problem • Compute for the pOH and pH of the solution if the OH- concentration is 12.1 x 10-10. • Given: pOH = 9.10, find OH- concentration.
  33. 33. pH and pKa values • Ka: is a quantitative measure of the strength of an acid in solution. • Very strong acids pKa < 1 • Moderately strong acids pKa = 1-5 • Weak acids pKa = 5-15 • Extremely weak acids pKa> 15
  34. 34. Buffer • Buffers is a solution in which the pH of the solution is "resistant" to small additions of either a strong acid or strong base. Composed of a weak acid and its conjugate base (e.g. CH3COOH and CH3COO-) or a weak base and its conjugate acid (e.g. NH3 and NH4 +). • Ex: Blood • Buffer capacity
  35. 35. Acid-base titration: Neutralization • Titration: The process of obtaining quantitative information on a sample using a fast chemical reaction by reacting with a certain volume of reactant whose concentration is known. aka _____________________ • Titrant: the known solution is added from a buret to a known quantity of the analyte until the reaction is complete • Endpoint: point at which the reaction is observed to be completed
  36. 36. Units of Measurement m/s seconds meters timeofunits distanceofunits velocityofUnits    SI Units  There are two types of units: – fundamental (or base) units; – derived units  There are 7 base units in the SI system.  Derived units are obtained from the 7 base SI units.
  37. 37. Units of Measurement SI Units
  38. 38. Units of Measurement SI Units
  39. 39. Temperature Units of Measurement
  40. 40. Units of Measurement Temperature  Kelvin Scale  Same temperature increment as Celsius scale  Lowest temperature possible (absolute zero) is zero K. Absolute zero: 0 K = -273.15oC  Celsius Scale  Water freezes at 0oC and boils at 100oC.  To convert: K = oC + 273.15  Fahrenheit Scale  Not generally used in science.  Water freezes at 32oF and boils at 212oF
  41. 41. Temperature Converting between Celsius and Fahrenheit Sample problem. Convert the following: 1. 257°F to °C 2. 75°C to °F and K  32-F 9 5 C    32C 5 9 F  Units of Measurement
  42. 42. Volume  The units for volume are given by (units of length)3. –i.e., SI unit for volume is 1 m3  A more common volume unit is the liter (L) –1 L = 1 dm3 = 1000 cm3 = 1000 mL  We usually use 1 mL = 1 cm3 Units of Measurement
  43. 43. Mass  Mass is the measure of the amount of material in an object. –This is not the same as weight which is dependent on gravity. Units of Measurement
  44. 44.  All scientific measures are subject to error.  These errors are reflected in the number of figures reported for the measurement.  These errors are also reflected in the observation that two successive measures of the same quantity are different. Uncertainty in Measurement
  45. 45. Precision and Accuracy  Measurements that are close to the “correct” value are accurate.  Measurements which are close to each other are precise. Measurements can be: – accurate and precise – precise but inaccurate – neither accurate nor precise Uncertainty in Measurement
  46. 46. Precision and Accuracy Uncertainty in Measurement
  47. 47. Uncertainty in Measurement Significant Figures - The number of digits reported in a measurement reflect the accuracy of the measurement and the precision of the measuring device. Remember the following:  Non-zero numbers are always significant.  Zeroes between non-zero numbers are always significant.  Zeroes before the first non-zero digit are not significant.
  48. 48. Uncertainty in Measurement Remember the following:  Zeroes at the end of the number after a decimal place are significant.  Zeroes at the end of a number before a decimal place are ambiguous. –10,300 has 3 significant figures. –10,300. has 5 significant figures.  Physical constants are “infinitely” significant.
  49. 49. Uncertainty in Measurement Significant Figures • Addition / Subtraction – The result must have the same number of digits to the right of the decimal point as the least accurately determined data. Example:  15.152  1.76  7.1 15.152 + 1.76 + 7.1 = 24.012 24.0
  50. 50. Uncertainty in Measurement Significant Figures • Multiplication / Division – The result must have the same number of significant figures as the least accurately determined data. Examples:  12.512  5.1 12.512 x 5.1 = ____ Answer has only 2 significant figures
  51. 51. Review on General Chemistry • Molecule – smallest particle of matter that can exist independently and still retain the properties of a larger mass of substance. • Atomic Number • Mass Number = P + N
  52. 52. Review on General Chemistry Problem: • Looking up with Co • Look for the number of neutron • Given: M = 59 Atomic Number (Z) = 27 Answer: 32 neutrons Operation to be used: M = P + N Solution: 59 = 27 + N N = 59 – 27 N = 32
  53. 53. Review on General Chemistry Problem: Radioactive Iodine • State the radioactive substance containing iodine with 78 neutrons • Answer: 131 • Operation: M = P + N • Solution: M = 53 + 78 M = 131 = I131
  54. 54. Definition of Terms • Atomic Weight – the average weight of the natural atoms of an element existing as a mixture of isotopes • Isotopes – nuclides or elements having the same number of protons (same atomic number) but different no. of neutrons (different mass numbers)
  55. 55. Definition of Terms •Allotropes – different forms of the same elements existing in the same physical state. •Alloy – a combination of 2 or more metals with properties more describe than any single metal.
  56. 56. ATOMIC THEORY • Scientific theory of the nature of matter, which states that matter is composed of discrete units called atoms. • Atoms are composed of central nucleus surrounded by electrons which occupy discrete regions of space. • The nucleus contains 2 types of stable particles which comprise most of the mass of an atom.
  57. 57. Dalton’s Atomic Theory • Matter is composed of tiny indivisible, indestructible particles called atoms. • Atoms of an element are the same, but they differ from atoms of other elements. • Atoms of two or more elements combine to form compounds in ratios of whole numbers. • A chemical reaction involves a rearrangement of atoms • Atoms cannot be created nor destroyed.
  58. 58. Remember the following: • Quantum Theory or Wave Theory (Erwin Schrodinger) relates that an electron is not a particulate but a quantity. • Atomic Orbitals – are volumes of space about the nucleus where the electron revolves.
  59. 59. Remember the following: •Neils Bohr
  60. 60. Remember the following: • Heisenberg Uncertainty Principle – states that it is not possible to fix simultaneously the momentum and the position of an electron. • Aufbau Principle – is the progressive building up of electronic configuration.
  61. 61. Remember the following: • Pauli’s Exclusion Principle – states that in any atom, no two electrons may be described by the same set of values for the four quantum numbers. • Hund’s Rule
  62. 62. Remember the following: •Valence electron • Octet Rule – state that the maximum number of electrons that can be present in the outermost level is eight which represents a stable configuration.
  63. 63. Remember the following:
  64. 64. Practice Set • Given, Chlorine with the A = 35 and Z = 17. • Find: Number of electrons, protons and neutrons • Draw the electronic configuration mnemonics • Using the given above, find the following: ▫ Electronic configuration ▫ Orbital diagram ▫ Core configuration ▫ Graphical diagram ▫ Valence number
  65. 65. Practice Set • Given: Boron, Nitrogen, Phosphorus • Find the following: ▫ Electronic configuration ▫ Orbital diagram ▫ Core configuration ▫ Graphical diagram ▫ Valence number
  66. 66. Part II: Organic Chemistry
  67. 67. INORGANIC CHEMISTRY  is the branch of chemistry concerned with the properties and behavior of inorganic compounds. Inorganic vs. Organic Chemistry
  68. 68. The Periodic Table
  69. 69. ORGANIC CHEMISTRY  is the branch of chemistry which deals with carbon- containing compounds. Inorganic vs. Organic Chemistry
  70. 70. Organic Chemistry  Formerly defined as the branch of science concerned with substances derived form living things.  Vital Force Theory – that organic substances could only originate from living material.  Friedrich Wöhler – disabuse the vital force concept (1828).
  71. 71. Organic vs. Inorganic Compounds CRITERIA ORGANIC COMPOUNDS INORGANIC COMPOUNDS Source Living/Non-living things Non-living things Elements C, H, O, N, P, S, Si, X All Chemical bond ? ? Solubility 1. Water/Polar Solvent 2. Organic/ Non- polar Solvent Soluble Soluble Insoluble Insoluble Boiling point Low High
  72. 72. CRITERIA ORGANIC COMPOUNDS INORGANIC COMPOUNDS Melting Point Low High Conductivity Poor conductor Good conductor Reaction to Ignition Flammable Non-flammable Rates of Reaction: 1. RT 2. High Temp. 3. Catalyst Slow Moderately fast to explosive Often needed Fast Very fast Seldom Organic vs. Inorganic Compounds
  73. 73. Common Terminologies in Organic Chemistry refer to your notes 
  74. 74. Carbon: The Chemical Basis for Life  From the Latin word “carbo” meaning charcoal.  Group __ element  IUPAC classification: Group __ element  Symbol: ___  Atomic no.: ___
  75. 75.  AMU: 12.0107  MP: ~3550°C  BP: 4827°C  SP: 3800°C  Density: 2.62 g/cm3  Valence No.: 4  Covalency No.: 4  Hardest form of carbon?  Softest form?  C14- useful in radiocarbon dating  Pure C is non-toxic Carbon: The Chemical Basis for Life
  76. 76. Allotropes of Carbon
  77. 77.  Fullerene  antioxidant  Amorphous Carbon  adsorbent Allotropes of Carbon
  78. 78.  Crystal Structure: Hexagonal  Electronic configuration Carbon Facts
  79. 79. HYBRIDIZATION  Defined as the phenomenon of mixing of atomic orbitals of nearly equivalent energy, involving redistribution of energy, to form new orbitals of equal energy known as hybrid orbitals.
  80. 80. HYBRIDIZATION
  81. 81. Hybrid Orbitals  Developed by Linus Pauling, the concept of hybrid orbitals was a theory create to explain the structures of molecules in space.  It consist of combining atomic orbitals (ex: s, p, d, f) into a new hybrid orbitals (ex: sp, sp2, sp3). It is an orbital created by the combination of atomic orbitals in the same atom.
  82. 82.  Atomic orbital  an expected region of electron density around an atom based on a solution to the Schrödinger wave function. Hybridization  the combining of solutions to the Schrödinger wave function for atomic orbitals to produce hybrid orbitals. Terminologies
  83. 83. Orbitals
  84. 84. s-orbital p-orbitals bond side ways overlap end to end overlap of orbitals leads to σ -bond σ -bond HYBRIDIZATION
  85. 85. Types of Carbon Hybrid Orbitals  sp3 hybrid or tetrahedral hybrid  sp2 hybrid or trigonal planar hybrid  sp hybrid or linear hybrid
  86. 86. Types of Carbon Hybrid Orbitals  sp3d hybrid  sp3d2 hybrid
  87. 87. sp3 hybrid  *C6 1s2 2s1 2px1 2py1 2pz1 pure AO  hybrid AO  (2sp3)1 (2sp3)1 (2sp3)1 (2sp3)1 2s 2px2py 2pz + + + 4 X sp3
  88. 88. 109.50 sp3 hybridized carbon 4 equivalent C-H bonds (s-bonds) All purely single bonds are called s-bonds Methane is Tetrahedral
  89. 89. sp2 hybrid or Trigonal hybrid  *C6 1s2 2s1 2px1 2py1 2pz1 pure AO  (2sp2)1(2sp2)1 (2sp2)1 2pz1 hybrid AO
  90. 90. sp hybrid or Linear hybrid  *C6 1s2 2s1 2px1 2py1 2pz1 pure AO  (2sp)1(2sp)1 2py1 2pz1 hybrid AO
  91. 91. Questions on Hybridization
  92. 92. PACOP QUESTION  What are the hybridizations of the orbitals between carbons 3 and 4 in the molecule CH2= CHCH2CH2CH3? A. sp2 – sp3 B. sp2 – sp2 C. sp3 – sp3 D. sp – sp2 E. sp3 – sp
  93. 93.  What are the hybridizations of the orbitals between carbons 1 and 2 in the molecule CH2= CHCH2CH2CH3? A. sp2 – sp3 B. sp2 – sp2 C. sp3 – sp3 D. sp – sp2 E. sp3 – sp PACOP QUESTION
  94. 94. Identify the Hybridization CH3CH2CH=CHCH2CCH
  95. 95. Identify the Hybridization
  96. 96. Identify the Hybridization
  97. 97. Identify the Hybridization
  98. 98. Bond Strength or Bond Energy  Is the energy necessary to break a bond in a diatomic molecule or to dissociate the bonded atoms to their ground state.
  99. 99.  Bond Length and Bond Polarity  As the bond polarity increases, the bond length decreases  Hybrid Orbitals and Bond Length  As s character increases, the bond length decreases Remember the following:
  100. 100.  Hybrid Orbital, Bond Length and Bond Polarity  When the s character of the bonding orbitals increases, the bond energy also increases  When the polarity of a bond increases, the bond energy also increases  Bond energy and bond length are inversely related Remember the following:
  101. 101. Hydrocarbon and derivatives
  102. 102. Hydrocarbons • Hydrocarbons are the simplest organic compounds. • Hydrocarbon derivatives are formed when there is a substitution of a functional group at one or more of these positions.
  103. 103. Hydrocarbon Derivatives • An almost unlimited number of carbon compounds can be formed by the addition of a functional group to a hydrocarbon.
  104. 104. Type or General Formula Class Type formula Alkane CnH2n+2 Alkene CnH2n Alkyne CnH2n-2 Cycloalkane CnH2n Cycloalkene CnH2n-2 Cycloalkyne CnH2n-4
  105. 105. Cyclopropane Cyclohexane Cyclobutane Cyclooctane
  106. 106. Aromatic Ar-H Alkyl halide R-X Aryl halide Ar-X Alcohol R-OH  Primary alcohol R-CH2-OH  Secondary alcohol R2-CH-OH  Tertiary alcohol R3-C-OH Type or General Formula
  107. 107. Who discovered the structure of benzene? Friedrich August Kekule
  108. 108. Phenol Ar-OH Ether R-O-R Aldehyde R- CHO Ketone R-CO-R Type or General Formula
  109. 109. Amine R-NH2 10 amine R-CH2-NH2 20 amine R-CH2-NH-R 30 amine R-CH2-N-R2 40 amine R-CH2-N+-R3 Type or General Formula
  110. 110. Carboxylic acid R-COOH Acid halide R-CO-X Acid amide R-CO-NH2 Acid anhydride R-CO-O-CO-R’ Ester R-COOR’ Nitro R-NO2 Type or General Formula
  111. 111. Nitroso R-N = O Nitrile (cyanide) R-C  N Imine Imide Type or General Formula
  112. 112. Diazo Hydrazino R-NHNH2 Mercaptan (thiol) R-SH Thioether R-S-R Enol Type or General Formula
  113. 113. The chemical CH3CH2COOCH3 is an example of what type of organic compound? A. Ketone B. Ester C. Ether D. Aldehyde E. Acid anhydride PACOP QUESTION
  114. 114. What is the type formula for ethers? A. RH B. RX C. ROR D. RCHO E. RCOOR PACOP QUESTION
  115. 115. The compound with the formula CH3CH2COCH2CH3 is a/an: A. Ketone B. Aldehyde C. Carboxylic acid D. Ether E. Ester PACOP QUESTION
  116. 116. The structure shown below is: C C C C C C H H H H HH =
  117. 117. Naphthalene Anthracene Phenanthrene The structure shown below is:
  118. 118. Isomers • compounds having the same molecular formula but different structural formulas.
  119. 119. Types of Isomers • Constitutional or Structural isomers ▫ Isomers with different atom to atom bonding sequencing. • Stereoisomers ▫ Isomers with the same atom to atom bonding sequence but with the atoms arranged differently in space.
  120. 120. Types of Structural Isomers • Chain isomers or skeletal isomers • Positional isomers • Functional isomers ▫ Tautomers
  121. 121. • Chain/Skeletal isomers ▫ Compounds that differ in the arrangement of carbons. Types of Structural Isomers
  122. 122. • Positional isomers ▫ Differ in the position of a non carbon group. Types of Structural Isomers
  123. 123. • Functional Isomer ▫ Differ in the functional group. Types of Structural Isomers
  124. 124. •2-pentanol and 3-pentanol are: A. Functional isomers B. Positional isomers C. Chain isomers D.Optical isomers E. Stereoisomers PACOP QUESTION
  125. 125. •2 - pentanol ▫ CH3CHOHCH2CH2CH3 •3 - pentanol ▫ CH3CH2CHOHCH2CH3 Answers:
  126. 126. STEREOISOMERS • Configurational or Inversional Isomers ▫ Compounds that can be interconverted by the breaking of chemical bond. • Conformational Isomers aka rotamers ▫ Interconvert easily at room temperature through rotation about single bond.
  127. 127. Types of Configurational Isomers • Enantiomers or enantiomorphs ▫ Stereoisomers that are non – superimposable mirror images of each other; rotate the plane polarized light in the opposite direction.
  128. 128. • Diastereomers ▫ Stereoisomers that are non – superimposable and non – mirror images of each other. Types of Configurational Isomers
  129. 129. Enantiomer vs. Diastereomers
  130. 130. • Geometric isomers (cis, trans) ▫ Cis-trans isomers – differ from each other in the orientation of atoms/groups on a carbon-carbon double bond or in a ring. Types of Configurational Isomers
  131. 131. trans vs. cis isomers
  132. 132. •Enantiomers differ from one another in: A.Spatial configuration B.Rational formula C.Ion-pair formation D.Photoelectric effect PACOP QUESTION
  133. 133. R vs. S Configuration Cahn-Ingold-Prelog system Determines R or S designation of enantiomers
  134. 134. Chiral or Asymmetric Center • Chiral or Asymmetric Center ▫ a molecule which contains a carbon to which four different groups are attached.
  135. 135. Identify which is the Chiral carbon
  136. 136. What type of isomerism is this?
  137. 137. Tautomers • Isomers that differ from each other in the position of hydrogen atom and double bond.
  138. 138. •Propanone and 1 – propen-1-ol are considered; A. Positional isomers B. Configurational isomers C. Tautomers D.Enantiomers E. Chain isomers PACOP QUESTION
  139. 139. Tautomers
  140. 140. • They are diastereomers that differ only in the position of moieties at the first carbon atom. Anomers
  141. 141. Meso Compound • one whose molecules are superimposable on their mirror images, even though they contain chiral centers.
  142. 142. Racemic Mixture • mixture of equimolar concentration of enantiomers in a solution.
  143. 143. IUPAC System Nomenclature •STEP 1: Name the Parent name. • Select the longest continuous chain. Hexane
  144. 144. •STEP 2: Number the Cs in the chain, from either end, such that the substituent are given the lowest #s possible. IUPAC System Nomenclature
  145. 145. • STEP 3: Substituent(s)/side chain(s) ▫ Identify the substituent(s) ▫ assigned the # of the C to which it is attached 3 - methyl IUPAC System Nomenclature
  146. 146. • STEP 4: Name of the compound • # of the substituent • name of the substituent • parent chain • # is separated from the name with hyphen • #s are separated from each other by comma 3 - methylhexane
  147. 147. STEP 5: If substituent occurs more than once in the molecule, the prefixes, di, tri, tetra, etc are used STEP 6: If a substituent occurs twice on the same carbon, the # of the C is repeated twice STEP 7: If two or more substituents of different nature are present, they are cited in alphabetical order. 7- ethyl - 4,4’- dimethylundecane
  148. 148. Guide for Organic Nomenclature:
  149. 149. undec- dodec- tetradec- pentadec- hexadec- heptadec- nonadec- eicos- tridec- 11 12 13 14 15 16 17 octadec- 18 19 20 Prefix meth- eth- prop- but- pent- hex- oct- non- dec- 1 2 3 4 5 6 7hept- 8 9 10 Carbons CarbonsPrefix
  150. 150. Trivial Roots of Common Name of Aldehydes and Acids # of Carbon Trivial Root # of Carbon Trivial Root 1 form – 6 capro – 2 acet – 7 enanth – 3 propion – 8 capryl – 4 butyr – 9 pelargon – 5 valer – 10 capr –
  151. 151. • Give the IUPAC name of the given chemical formula CH3C(CH3)2CH2CH2NH2 A. 1-aminoheptane B. 1-amino-2,2-dimethylbutane C. 4-amino-2,2-dimethylbutane D. 1-amino-3,3-dimethylbutane E. 7-amino-1-monomethylpentane PACOP QUESTION
  152. 152. • Give the IUPAC name of the given chemical CH(OH)2CH2CH2CH2CH3 A. pentan-1,1-diol B. 1-dihydroxypentane C. 5,5-dihydroxypentanol D. pentanal E. 2,2-dipentanol PACOP QUESTION
  153. 153. • What is the type formula of the chemical methoxyethane? A. RCHO B. RCOOH C. RCOOR D. RCOR E. ROR PACOP QUESTION
  154. 154. Name the following:
  155. 155. Mechanism of Reaction: the detailed course of overall reaction. • Sequence of steps • Details of electron movement • Bond breaking • Bond making • Timing
  156. 156. • A + B [ C ] D + E ▫ A – substrate ▫ B – reagent ▫ C – intermediate ▫ D – main product ▫ E – side product Mechanism of Reaction: the detailed course of overall reaction.
  157. 157. Types of Bond Cleavage • Homolytic Cleavage ▫ Characterized by homolytic fission of bonds and the formation of free radicals.
  158. 158. • Heterocyclic Cleavage ▫ Characterized by heterocyclic fission and the formation of charged species. Types of Bond Cleavage
  159. 159. Types of Reagents •1. Nucleophiles (Nu:) ▫ electron-rich species ▫ electron pair donor ▫ attack positions with + charge or low electron density
  160. 160. •2. Electrophiles (E+) ▫ electron-poor species ▫ electron pair acceptor ▫ attack positions with - charge or high electron density ▫ H3O+, BF3, AlCl3, Br2, Cl2, I2 Types of Reagents
  161. 161. Types of Reaction Intermediates
  162. 162. Types of Organic Reactions • Substitution reaction • Addition reaction • Elimination reaction • Rearrangement reaction • Oxidation • Reduction
  163. 163. Substitution Reaction
  164. 164. Addition Reaction
  165. 165. Elimination Reactions
  166. 166. Rearrangement Reaction
  167. 167. Oxidation • increase in oxygen • Increase in electron • decrease in hydrogen
  168. 168. Reduction • increase in hydrogen • decrease in electron • decrease in oxygen
  169. 169. Atomic Bonds 1. Ionic bonding 2. Covalent bonding 3. Hydrogen bonding or bridging) 4. Van der Waals (London forces)
  170. 170. Ionic Bonding ▫ electrostatic interaction resulting from the transfer of an electron during the compound formation. Atomic Bonds
  171. 171. Covalent Bonding ▫ is the attractive force that exists between two chemicals entities due to their sharing a pair of electrons. Atomic Bonds
  172. 172. Hydrogen bonding (or bridging) ▫ Attraction between a lone pair of electrons of a highly electronegative atom and a hydrogen atom bonded to a high electronegative atom. Atomic Bonds
  173. 173. Vander Waals (London forces) ▫ these are very weak electrical force sometimes referred to as induced dipole – induced dipole interactions. ▫ The associations between aromatic hydrocarbon molecules such as benzene are due to Van der Waals forces Atomic Bonds
  174. 174. Other electrostatic attraction: a) Ion-dipole Interactions b) Dipole-dipole interactions c) Ion-induced dipole interactions d) Dipole-induced dipole interactions e) Induce dipole – induced dipole interactions Atomic Bonds
  175. 175. Alkanes (paraffins, saturated HC) • Lipid – soluble • Common reactions are: ▫ Halogenation ▫ Combustion • Upon storage, alkanes are chemically inert with regard to air, light, acids and bases • In vivo, alkanes are stable • Terminal carbon side – chain hydroxylation may occur
  176. 176. Alkenes (olefins, unsaturated HC) • Lipid soluble • Common Reactions are: ▫ Addition of hydrogen or halogen ▫ Hydration to form glycols ▫ Oxidation to form peroxides • Upon storage, volatile alkenes and peroxides may explode in the presence of oxygen and spark; in vivo, alkenes are relative stable • Hydration, Epoxidation, Peroxidation and Oxidation may occur
  177. 177. Aromatic Hydrocarbons • Based on benzene, exhibit multicenter bonding which confers unique chemical properties • Lipid soluble • Common reactions are electrophillic substitution such as: ▫ Halogenation, Nitration, Sulfonation, Alkylation • Upon storage, ArHC are stable • In vivo, ArHC undergo Hydroxylation, Epoxidation, diol formation
  178. 178. Alkyl Halides • Also known as Halogenated HC • Lipid soluble • Common reactions are: ▫ Nucleophillic substitution ▫ Dehydrohalogenation • Upon storage, alkyl halides are stable • In vivo, alkyl halides are not readily metabolized
  179. 179. Alcohols • Lipid soluble ▫ LMW Alcohols are water soluble  Water solubility decreases as HC chain length increases • Common reactions: esterification and oxidation ▫ 1° alcohols – oxidized to aldehydes then to acid ▫ 2° alcohols – oxidized to ketones
  180. 180. •Upon storage, alcohols are stable •In vivo, alcohols may undergo ▫ Oxidation ▫ Glucoronidation ▫ Sulfation Alcohols
  181. 181. Phenols • Lipid soluble • Fairly soluble in water – ring structure decrease water solubility • Common reactions: ▫ With strong base to form phenoxide ion ▫ With acids esterification ▫ Oxidation to form quinines, usually colored
  182. 182. • Upon storage, phenols are susceptible to: ▫ Air oxidation ▫ Oxidation on contact with ferric ions (FeCl3) • In vivo, phenols undergo: ▫ Sulfation ▫ Glucoronidation ▫ Aromatic hydroxylation ▫ O - methylation Phenols
  183. 183. Important Alcohols and Phenols • Methanol • Ethanol • Isopropyl alcohol • Cholesterol • Glycerol • Ethylene glycol • Phenol • Cresol • Resorcinol • Hexylresorcinol • Menthol • Geraniol • Glucose
  184. 184. Ethers • Lipid soluble ▫ LMW ethers are partially water soluble  Water solubility decreases with an increase in HC • Common reaction is oxidation to form peroxides • Upon storage, peroxides may explode • In vivo, ethers undergo O-dealkylation ▫ Stability increases with the size of the alkyl group
  185. 185. Important Ethers • Ether: used before as general anesthetic agent ▫ ADR: irritation of mucous membranes, N & V • Ethylene oxide: used as gas sterilant for things that cannot be autoclaved • Eugenol
  186. 186. Aldehydes • Lipid soluble ▫ LMW are water soluble • Common reactions are: ▫ Oxidation ▫ Hemiacetal and acetal formation • In vivo, aldehydes may also undergo oxidation to acids or reduction to alcohols
  187. 187. Important Aldehydes • Formaldehyde • Acetaldehyde • Chloral hydrate • Benzaldehyde • Cinnamaldehyde • Vanillin • Citral
  188. 188. Ketones • Lipid Soluble ▫ LMW are water soluble • Relatively non – reactive, but may exist in equilibrium with their enol forms • Upon storage, ketones are very stable • In vivo reaction includes: Oxidation, Reduction
  189. 189. Amines • Contains an amino group ▫ Amino group can exist in ionized or un- ionized form. • Lipid soluble ▫ LMW amines are water soluble  Solubility decreases with an increase branching  Quaternary amines, being ionic are water soluble
  190. 190. • Common reactions: ▫ Oxidation ▫ For alkyl amines salt formation with acids ▫ Aromatic amines, which are less basic, have less tendency to react with acids • Upon storage phenolic amines are susceptible to air oxidation • In vivo, amines may undergo minor glucoronidation, sulfation, and methylation Amines
  191. 191. • Primary amines also undergo oxidative deamination • Primary and secondary amines undergo acetylation • Secondary and tertiary amines undergo N-dealkylatin • Tertiary amines, least water soluble undergo N-oxidation Amines
  192. 192. Carboxylic acids • Lipid soluble ▫ LMW carboxylic acids are water soluble (Na, K salts) • Common reactions are: ▫ Salt formation with bases ▫ Esterification ▫ Decarboxylation
  193. 193. • On the shelf, carboxylic acids are very stable • In vivo, carboxylic acids undergo ▫ Conjugation with glucoronic acid, glycine and glutamine ▫ Beta oxidation Carboxylic acids
  194. 194. Important Carboxylic acids • Salicylic acid • Citric acid • Lactic acid • Tartaric acid • Benzoic acid • ASA • PABA
  195. 195. Esters • Lipid soluble ▫ LMW esters are slightly water soluble • Common reactions of esters is hydrolysis • Upon storage: ▫ Simple or LMW esters are susceptible to hydrolysis ▫ Complex or HMW or water – insoluble esters are resistant • In vivo, esters undergo enzymatic hydrolysis by esterases
  196. 196. Amides • Lipid soluble ▫ LMW are fairly soluble in water • No common reactions • Upon storage they are stable • In vivo, they undergo enzymatic hydrolysis by amidases
  197. 197. Important Amides •Acetanilide •Niacinamide or nicotinamide •Sulfanilamide
  198. 198. Part III: Organic Medicinal Chemistry Mr. Jan Dominique R. Lapig, RPh April – May 2014
  199. 199. Medicinal Chemistry “…let’s make a change on an existing compound or synthesize a new structure and see what happens…”
  200. 200. What is Medicinal Chemistry? • Medicinal Chemistry is a chemistry-based discipline, involving the aspects of biological, medical and pharmaceutical sciences.
  201. 201. What is Medicinal Chemistry? • Medicinal Chemistry devoted to the discovery and development of new agents for treating diseases. - Wilson and Gisvold’s 12th ed.
  202. 202. Synthetic Chemistry • involves changes designed to transform a starting substance with a particular set of properties.
  203. 203. Definition of Drug • Is a chemical compound that is used to treat, mitigate, diagnose and prevent diseases both in humans and animals • Compounds that interact with a biological system to produce a biological response • Currently, there is no drug that is considered to be totally safe • Some poison at low doses can be used as drugs; drugs at high concentration can be considered as poison
  204. 204. New Field in Medicinal Chemistry: Biotechnology • Modified Human Insulin – convenient dosing • Cell – Stimulating Factors – dosing regimen for chemotherapy • Humanized Monoclonal Antibodies – target specific tissues • Fused Receptors – intercept immune cell-generated cytokinases
  205. 205. • Antitoxin – a type of immunobiological that contains a solution of antibodies derived from the serum of animals immunized with specific antigen. • Intravenous immunoglobulin (IVIg) – a product derived from blood plasma of a donor pool similar to the IG pool but prepared so it is suitable for IV use. New Field in Medicinal Chemistry: Biotechnology
  206. 206. •Toxoid – a modified bacterial toxin that has been made nontoxic but remains the ability to stimulate the formation of anti-toxin. New Field in Medicinal Chemistry: Biotechnology
  207. 207. Recall the following principles in understanding medicinal chemistry: • Physicochemical properties used to develop new pharmacologically active compounds; • Their mechanism of action; • The drug's metabolism; • Possible biological activities of the metabolites; • Importance of stereochemistry in drug design; • The methods used to determine what “space” a drug occupies.
  208. 208. Physicochemical properties of lead compounds can provide new drugs: •Cimetidine ▫ as an antinuclear antibody test/drug ▫ Antinuclear antibody (ANA) test measures the amount and pattern of antibodies in the blood that work against the body (autoimmune reaction).
  209. 209. Answer on Pre-Test • As of the present, it is the most used and productive method of obtaining new drugs: A. Random screening B. Extraction from natural resources C. Serendipity D. Molecular manipulation E. Drug discovery by “luck”
  210. 210. Early Drug Discovery • Random sampling of higher plants: Opium, belladona, ephedrine • Accidental discovery: Penicillin • The use of nutriceuticals or the non-traditional or alternative medicinal agents
  211. 211. Receptors • substance to which a drug needs to interact with to elicit pharmacologic response • a relatively small region of a macromolecule which may be an/a: ▫ Enzyme ▫ Structural or functional group/component of CM, ▫ Specific intracellular substance such as proteins and nucleic acids
  212. 212. Remember the following terms: • AFFINITY : ability of a drug to bind with a receptor. • INTRINSIC ACTIVITY: ability of a drug to exert a pharmacologic action. • AGONIST: drug with affinity and intrinsic activity. ▫ Description of agonist: mimic the natural ligand for a receptor and may have similar structure to the ligand
  213. 213. • INVERSE AGONIST: these are exogenous chemical messengers that acts as antagonist, but also eliminate any resting activity associated with a receptor • ANTAGONIST: drug with affinity but does not have intrinsic activity ▫ Description of antagonist: they bind to regions of the receptor that are not involved in binding the natural ligand. Remember the following terms:
  214. 214. • AGONIST–ANTAGONIST: in the presence of antagonist, its effect is agonist, in the absence of an agonist its effect is agonist. • SENSITIZATION: occur when an antagonists is bound to a receptor for a long period of time. The cell synthesize more receptors to counter the antagonistic effects. • DESENSITIZATION: this condition may occur when an agonist is bound to its receptor for a long period of time Remember the following terms:
  215. 215. •TOLERANCE: it is a situation where increase doses of a drug are required over time to achieve same effect •DEPENDENCE: it refers to the body’s ability to adapt to the presence of a drug. Remember the following terms:
  216. 216. •EFFICACY: it is determined by measuring the maximum possible effect resulting from receptor-ligand binding. •POTENCY: relates how effective a drug is in producing a cellular effect. Remember the following terms:
  217. 217. Drug Classification • Pure organic compounds are the chief source of agents for the cure, mitigation or the prevention of disease. • These remedial agents could be classified according to their origin: ▫ Natural compounds ▫ Synthetic compounds ▫ Semi – synthetic compounds
  218. 218. • Pharmacodynamic agents: Drugs that act on the various physiological functions of the body (e.g. general anesthetic, hypnotic and sedatives, analgesic etc.). • Chemotherapeutic agents: Those drugs which are used to fight pathogens (e.g. sulfonamides, antibiotics, anti – malarial agents, antiviral, anticancer etc.). Drug Classification
  219. 219. • Drugs can treat different types of diseases: ▫ Infectious diseases: Born (transmitted) from person to person by outside agents, bacteria (pneumonia, salmonella), viruses (common cold, HIV), fungi (thrush, athletes foot), parasites (malaria). Drug Classification
  220. 220. ▫ Non-infectious diseases: disorders of the human body caused by genetic malfunction, environmental factors, stress, old age etc. (e.g. diabetes, heart disease, cancer, hemophilia, asthma, mental illness, stomach ulcers, arthritis). ▫ Non-diseases: alleviation of pain (analgesic), prevention of pregnancy (contraception), anesthesia. Drug Classification
  221. 221. Drug Development
  222. 222. Life Cycle for new drug :
  223. 223. IND Program • Pharmaceutical company obtains permission to ship an experimental drug to clinical investigators before a marketing application for the drug has been approved. • FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk. • If the application is approved, the candidate drug usually enters a Phase 1 clinical trial.
  224. 224. Pre CLINICAL TRIALS: • Evaluation of acute and short term toxicity in animals. It Involves : -Lethal dose determination -Effect of dose at normal level for short/Long term • Assess how the drug is: absorbed/distributed/metabolized and excreted in animals.
  225. 225. Phase 0 CLINICAL TRIALS • Parameters measure: PD and PK testing especially oral bioavailability and half life (T½) • Dose of investigational drug is very small, usually sub-therapeutic dose, involving 10 human subjects • Often skipped for phase I
  226. 226. Phase 1 CLINICAL TRIALS • Begins after 30 days of filing IND. • Drug given to 20-100 healthy volunteers ▫ Duration could vary from 1 month to 1 year. • Following is studied here : ▫ Drug absorption/Metabolism in human. ▫ Effect on organs and tissues. -Side affect of different dosages. ▫ Thus early evidences on effectiveness are achieved.
  227. 227. Phase 2 CLINICAL TRIALS • Drug given to 100 - 500 patient volunteers • Duration could vary from 1 year to 2 years ▫ Following are measured/ studied here:  Safety  Drug effectiveness in treating the disease  Short term side effects in patients  Dose range  Less than 1/3 of INDs survive phase 2
  228. 228. Phase 3 CLINICAL TRIALS • FDA consulted before beginning phase 3 ▫ Drug given to 1000-5000 patient volunteers ▫ Duration could vary from 3 years to 4 years. • Following are measured/studied here : ▫ Safety of Drug [ Benefits vs. risk analysis ] ▫ Effectiveness possible long term side effects in patients ▫ Dosing and labeling information
  229. 229. NDA • Formal proposal for the FDA to approve a new drug for sale in the U.S. • Sufficient evidences provided to FDA to establish: ▫ Drug is safe and effective. ▫ Benefits outweigh the risks. ▫ Proposed labeling is appropriate.
  230. 230. Historical Timeline: Elixir 1906 1937 No Regulatory control for Drug safety Sulfanilamide disaster Federal Food and Drug Act passed 1938 1961 Thalidomide crisis
  231. 231. Phase 4 : Post Marketing Surveillance • Launched to the Market • Additional post marketing testing of patients to ▫ Support the use of the approved indication ▫ Finding new therapeutic opportunities ▫ Extending use of the drug to different classes of patients like children.
  232. 232. Discovery & Development of Organic Medicinal Chemicals: •Random screening – (with enzyme linked assays or receptors from gene cloning) of existing drugs lead to identification of new LEAD drug. ▫ e.g. Amantadine
  233. 233. • Rational Drug Design- opposite approach to high-volume screening using techniques like: ▫ X-ray crystallography ▫ Nuclear magnetic resonance • Leads to the development of drugs; ▫ HIV protease inhibitor ▫ ACE inhibitors ▫ H2 antagonists Discovery & Development of Organic Medicinal Chemicals:
  234. 234. Helpful mnemonics
  235. 235. •Biotechnology techniques a. Recombinant DNA b. Mutagenesis- site directed that fuse cell lines Discovery & Development of Organic Medicinal Chemicals:
  236. 236. Sources of Drugs • PLANT SOURCES -Random sampling of higher plants led to the discovery of crude plant drugs. • e.g. opium, belladona, ephedrine ephedrineAtropa belladona
  237. 237. •ANIMAL SOURCES: Glandular products from animals are used, such as insulin and thyroid. Sources of Drugs
  238. 238. • BACTERIAL AND FUNGAL SOURCES ▫ Alexander Fleming (1929)- presented his findings of staph. Inhibited in a petri dish by the mold Penicillium notatum (PENICILLIN). ▫ Florey & Chain (1941)- isolated penicillin using freeze drying and chromatography; took one step further by injecting Penicillium notatum on a live mice. With controlled experimentation, they found it cured mice with bacterial infections. Sources of Drugs
  239. 239. • MINERAL SOURCES: Some drugs are prepared from minerals: ▫ e.g. KCl, and lithium carbonate (an antipsychotic). • SYNTHETIC SOURCES: Laboratories duplicate natural processes. • Frequently this can eliminate side effects and increase the potency of the drug. ▫ e.g. barbiturates, sulfonamides, ASA. Sources of Drugs
  240. 240. Drug Nomenclature • Standardized prefixes, infixes or suffixes in GENERIC names are used to classify & relate new chemical entities to existing drug families. • Stems- are standardized syllables that can emphasize a special chemical nucleus, pharmacological property, or combination of these attributes.
  241. 241. 1. Chemical Name- usually applied to compounds of known composition using the Chemical Abstract Services (CAS index). 2. Biochemical, botanical or zoological name- substance of plant or animal origin that cannot be classified as pure chemical compounds. Drug Name Types:
  242. 242. 3. Trademark name- developed by the manufacturer; selected for their ease of recall but does not give a scientific information about the drug. 4. Nonproprietary name/ Generic Name- a single, simple, informative designation available for unrestricted public use. Specific for a given compound even though it may possess a stem common to a related group of drug. Drug Name Types:
  243. 243. 1. CHEMICALLY DERIVED STEMS  PREFIX cef- (cephalosphorins) cefotetan, cefixime  INFIX -nab- (cannabinols) dronabinol, tinabinol  SUFFIX –azoles (antifungal imidazole) ketoconazole, fluconazole, itraconazole. Naming of Drugs
  244. 244. 2. PHARMACOLOGICALLY DERIVED STEM e.g. *–statin (HMG CoA reductase inhibitor): lovastatin *–vir (antiviral agents): acyclovir, ribavirin *–astine (histamine antagonist): acrivastine, temelastine, zepastine Naming of Drugs
  245. 245. 3.COMBINATION STEMS e.g. *–olol (beta blockers): timolol, atenolol, metoprolol *–profen (ibuprofen type; anti- inflammatory/analgesic agents): ibuprofen, ketoprofen Naming of Drugs
  246. 246. Terminologies • Lead compound: a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.
  247. 247. Terminologies • Orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.
  248. 248. Terminologies •Prodrug are compounds that are inactive in their native form but are easily metabolized to the active agent. ▫ 2 broad categories, (Wermuth) Carrier-linked prodrug Bio-precursors
  249. 249. Prodrug • Carrier-linked prodrug: consist of the attachment of a carrier group to the active drug to alter its physicochemical properties and then subsequent enzymatic or non enzymatic mechanisms to release the active drug moiety.
  250. 250. Prodrug ▫ Double prodrug, pro-prodrug or cascade latentiated prodrugs: only carried out by enzymatic conversion to prodrug is possible before the “pro-drug” release the active drug ▫ Macromolecular prodrug: use macrolomecules as carriers
  251. 251. •Site-specific prodrugs: where carrier acts as transporter of the active drug to a specific targeted site. Prodrug
  252. 252. List of some PRODRUGS • Carisoprodol is metabolized into _________. • Enalapril is bioactivated by ______ to the active _________. • Valaciclovir is bioactivated by ______ to the active _________. • Levodopa is bioactivated by __________ to the active _______.
  253. 253. List of some PRODRUGS • Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol, because pure chloramphenicol is poorly soluble in water (2.5mg/mL) or palmitate ester to make a suspension (1.05 mg/mL). • Heroin is deacetylated by esterase to the active _______.
  254. 254. • Azathioprine: designed to prolong the drug activity of its active metabolite • Cyclophosphamide: designed to mask the toxic side effects of the active metabolite • Hetacillin: designed to increase the chemical stability of the active metabolite List of some PRODRUGS
  255. 255. Codrug/Mutual prodrug • consists of two synergistic drugs chemically linked together, in order to improve the drug delivery properties of one or both drugs. • Examples: A. Sulfasalazine (sulfapyridine + 5- aminosalicylic acid) B. Benorylate (paracetamol + ASA) C. Sultamicillin (Ampicillin + sulbactam)
  256. 256. Question: • This route of administering drug involves absorption problem because this places the drug directly to the blood circulation. A. Subcutaneous B. Rectal C. Intravenous D. Oral
  257. 257. Oral Route IM or SQ Injection IV Injection Receptors for Desired EffectsGastrointestinal Tract Tissue Depots a SYSTEMIC CIRCULATIONSerum AlbuminDrug DRUG DRUG DRUG DRUG METABOLITES DRUG DRUG METABOLITES DRUG METABOLITES DRUG METABOLITES a DRUG METABOLITES Liver: major site of drug metabolism Bile Duct Intestinal Tract Kidney Receptors for Undesired Effects EXCRETION FECES
  258. 258. BIOLOGICAL EFFECT OF A DRUG • result of an interaction between the drug substance and functionally important cell receptors or enzyme systems.
  259. 259. DRUG ACTION • Results from the interaction of drug molecules with either normal or abnormal physiological processes. • The ability of a chemical compound to elicit a pharmacologic /therapeutic effect is related to the influence of its various physical and chemical (physicochemical) properties.
  260. 260. 1. Systematically active drugs must enter and be transported by body fluids. 2. Drug absorption, metabolism, utilization, and excretion all depend on the drug’s physicochemical properties and the host’s physiological, and biochemical properties.
  261. 261. • What is the rate – limiting step in drug absorption of orally administered solid dosage forms? A. Dissolution rate B. Metabolism C. Elimination rate D. B and C E. A and B Question:
  262. 262. Physicochemical Properties • Polarity • Acidity/Basicity • Dissolution • Particle size and Surface Are • Salt formation • Polymorphism • Chirality • Hydrates • Complex formation • Viscosity
  263. 263. Physicochemical Properties in Relation to Biological Action • The most pharmacologically influential physicochemical properties of organic medicinal agents (OMAs) are: A.Solubility (Polarity) B.Acidity and basicity C.Reactivity
  264. 264. Drug Polarity • Can be measured by __________ • Partition coefficient (P) of a drug is defined as the ratio of the solubility of the compound in an organic solvent to the solubility of the same compound in an aqueous environment. • USP values: >3.3% or ≈ logP ≤ +0.5 • Why consider this? ▫ Formulation of the drug in an appropriate dosage form, and ▫ Bio-disposition
  265. 265. Water Solubility • Presence of __ and __ containing functional group. • Water solubility is required for: ▫ Dissolution in the GI Tract ▫ Preparation of parenteral solutions (as opposed to suspensions) ▫ Preparation of ophthalmic solutions ▫ Adequate urine concentrations (pertains primarily to antibiotics)
  266. 266. Lipid Solubility • Enhanced by non-ionizable hydrocarbon chains and ring systems. • Lipid solubility is required for: ▫ Penetration through the lipid bilayer in the GI tract ▫ Penetration through the blood-brain barrier ▫ Preparation of IM depot injectable formulations ▫ Enhanced pulmonary absorption within the respiratory tract ▫ Enhanced topical potency ▫ Enhanced plasma protein binding
  267. 267. Lipophilic Hydrophilic Equally soluble OMAs More lipophilic OMAs More hydrophilic OMAs CHO2N OH CH CH2OH NH C O CHCl2 Lipophilic Lipophilic Hydrophilic Hydrophilic Hydrophilic Chloramphenicol
  268. 268. Solubility Prediction Soluble Insoluble
  269. 269. Solubility Prediction Compounds with log Pcalc values greater than +0.5 are considered water insoluble (lipophilic) and those with log Pcalc values less than +0.5 are considered water soluble (hydrophilic).
  270. 270. Acidity and Basicity • Ionization of acids and bases plays a role with substance that dissociate into ions. • The ionization constant (Ka) indicates the relative strength of the acid or base.
  271. 271. Consider the following regarding the pH of the medium and the acid/base property of a drug: • pKa is a property of the drug molecule in a solution while in pH is the property of the medium • Acidic drug will most likely be dissociated in a basic medium and vice versa • The sum of the negative logarithm of the dissociation constants of the acid and its conjugate base is always equal to 14
  272. 272. Consider the following: •Indomethacin pKa = 4.5 well absorbed in ____________. •Ephedrine pKa = 9.6 well absorbed in _____________.
  273. 273. Forces of Attraction • Van der Waals • Dipole-dipole bonding • Ionic bonding • Ion-dipole binding • Covalent bond • Reinforce ionic • Hydrogen bond • Hydrophobic bond
  274. 274. Physicochemical Properties • Polarity • Acidity/Basicity • Dissolution • Particle size and Surface Area • Salt formation • Polymorphism • Chirality • Hydrates • Complex formation • Viscosity
  275. 275. In general, for a drug to exert its biologic effect: • It must be transported by the body fluid; • Traverse the required biologic membrane barriers; • Escape widespread distribution to unwanted areas, endure metabolic attack; • Penetrate in adequate concentration to the sites of action; • Interact in a specific fashion, causing an alteration of cellular function.
  276. 276. Drug Absorption and Distribution • Absorption ▫ transfer of a drug from the site of administration into the systemic circulation or bloodstream • Oral Administration ▫ The drug must go into solution to pass through the gastrointestinal mucosa
  277. 277. Factors affecting ABSORPTION • Chemical nature of drug: ______ and ______ • Particle size: _______ • Nature (Crystalline vs. Amorphous) ▫ like in insulin: semi-lente has shortest activity (100% amorphous) while ultra lente has longest activity. • Tablet coating • Blood flow: ____ site of most drug absorption. ROH and ASA is best absorbed in ______ • Surface area • Contact time at the absorption surface
  278. 278. Drug Distribution • Parenteral Administration ▫ given to patient who cannot take or incapable of taking oral dosage forms ▫ bypass first pass metabolism ▫ Examples:  IV  IM/SQ  Instraspinal  Intracerebral
  279. 279. Blood-Brain Barrier • composed of membranes of tightly joined epithelial cells lining the cerebral capillaries. • the brain is not exposed to the same variety of compounds that other organs are. • e.g. local anesthetics (spinal block)
  280. 280. Factor affecting DISTRIBUTION • Protein Binding Drug + Albumin Drug-Albumin Complex • Major protein: ______ and α-acid glycoprotein • BOUND vs. UNBOUND • Example is Warfarin and Phenylbutazone: predict the drug-drug interaction
  281. 281. Protein Binding • Protein binding may also limit access to certain body compartments. e.g. placenta • Protein binding also can prolong the drug’s duration of action. How? • Protein binding limits the amount of drug available for biotransformation and for interaction with specific receptor sites. • e.g. suramin sodium
  282. 282. Tissue Depot • The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots. • Barbiturates activity
  283. 283. Importance of Drug Metabolism • The basic premise: • Lipophillic Drugs  Hydrophillic Metabolites (Not Excreted) (Excreted) • Generally pharmacologically inactive and • Non-toxic metabolites
  284. 284. METABOLISM • Chemical reaction that occur in the body to maintain life. • Allow organisms to grow and reproduce, maintain their structures, and respond to their environments. • Divided into two categories: • _________ breaks down organic matter • _________ uses energy to build up or construct components of cells such as proteins and nucleic acids.
  285. 285. METABOLISM • to supply energy for body functions and maintenance • plays a central role in the elimination of the drugs and xenobiotics • Goal is to convert drug into _________, ________, and _______ form that are readily excreted. • It is detoxification process. • ________ is the main site. • converts inactive drug to active form (prodrug approach) in a process called ____________.
  286. 286. Importance of Drug Metabolism •Xenobiotic metabolism: it is used to describe the protective biochemical process by which a living organism either enzymatically or non- enzymatically alters a xenobiotic to a metabolite that is inactive or quickly eliminated from the organism.
  287. 287. Importance of Drug Metabolism •Termination of Drug Action • Bioinactivation • Detoxification • Elimination
  288. 288. Importance of Drug Metabolism •Bioinactivation
  289. 289. Importance of Drug Metabolism •Detoxification
  290. 290. Importance of Drug Metabolism •Elimination
  291. 291. Importance of Drug Metabolism •Bioactivation • Active Metabolites • Prodrug • Toxification
  292. 292. Importance of Drug Metabolism •Active Metabolites
  293. 293. Importance of Drug Metabolism •Prodrug
  294. 294. Sites of Drug Biotransformation 2. Liver (hepatic metabolism or First Pass Effect The most important organ in drug metabolism 1. Gastrointestinal Tract Absorb orally administered drugs Some drugs may decrease Oral bioavailability Lidocaine (ineffective) Isoproterenol Meperidine Morphine Nitroglycerin Pentazocaine Propoxyphene Propranolol Salicylamide 3. Blood Circulation Absorb orally administered drugs
  295. 295. First-Pass Metabolism • Pre-systemic metabolism • It is a phenomenon of drug metabolism whereby the concentration of a drug is greatly affected or reduced before it reach systemic circulation • Limits oral availability of highly metabolized drugs.
  296. 296. General Pathways of Drug Metabolism •Phase I or Functionalization • provide functional groups (–OH, –COOH, –SH, –NH2) capable of undergoing Phase 2 reactions. • The enzymes are found in sub-cellular components including cytoplasm, mitochondria and endoplasmic reticulum.
  297. 297. General Pathways of Drug Metabolism • Usually results in loss of pharmacological activity • Sometimes may be equally or more active than parent. • Reactions includes: * Oxidative Reaction – Gain of Oxygen; Loss of hydrogen (functional group introduction) * Reductive Reaction * Hydrolytic Reaction
  298. 298. General Pathways of Drug Metabolism •Phase II or Conjugation Reaction – (Condensation reaction) •Goal: to attach small, polar, ionizable endogenous compounds to the “handles” of phase I metabolites resulting to the conjugated metabolites which is readily excreted in the urine and feces
  299. 299. Question •What will happened to drugs that are resistant to drug-metabolizing enzymes?
  300. 300. •Major enzyme system in the liver that is responsible for most of drug metabolism: A. Monoamine oxidase B. Cytochrome P450 C. Catalase D. Ligase E. Esterase Question
  301. 301. Mixed function oxidases or Monooxygenases Capital Letter Arabic Number family Capital Letter subfamily system Arabic Number enzyme
  302. 302. Oxidation • Requires NADP+, O2, microsomal fraction, and NADPH • Active toward broad spectrum of compounds • Incorporates only one O atom into the substrate • Involves a heme protein, which absorbs visible light of 450nm after reduction and exposure to CO • Name ___________
  303. 303. Oxidation •Oxidation is the addition of oxygen and/or the removal of hydrogen. •Hydroxylation is the introduction of an OH group by oxidation. •Example: aniline into ________
  304. 304. Reduction •Loss of oxygen ; Gain of Hydrogen • Chemical reaction in which the substrate gains electrons. • Reductions are most likely to occur with xenobiotics in which oxygen content is low. • Important in the metabolism of carbonyl to alcohol derivatives, nitro and azo group to amino acid derivatives.
  305. 305. Reduction Clonazepam • Nitroreductase • Bacterial reductase • Aldo-keto reductase • NADPH cytochrome-c- reductase ENZYMES
  306. 306. Hydrolysis • Common for drug with functional groups like esters and amides • Addition of water with breakdown of molecule • Functional group unmasking N H O N NH2N OH O + Lidocaine
  307. 307. Hydrolysis Procainamide • Esterases • Amidases • Phosphatase • Sulphatases • Expoxide hydroxylase ENZYMES
  308. 308. Non-CYP Drug Oxidation • Monoamine Oxidase (MAO) and Diamine Oxidase (DAO) • MAO (mitochondrial) oxidatively deaminates endogenous substrates including NT (dopamine, serotonin, norepinephrine, epinephrine); • Drugs designed to inhibit MAO used to effect balance of CNS neurotransmitters (L- DOPA); • DAO substrates include histamine and polyamines.
  309. 309. Non-CYP Drug Oxidation • Alcohol & Aldehyde Dehydrogenase non-specific enzymes found in soluble fraction of liver; ethanol metabolism • Alcohol Dehydrogenase - a cytosolic enzyme, promotes the oxidation of primary alcohol to aldehyde and secondary alcohol to ketones (a reversible process) • Aldehyde Dehydrogenase - cytosol, mitochondria: oxidation of aldehyde to carboxylic acid seen on ethanol metabolism
  310. 310. Non-CYP Drug Oxidation •Xanthine Oxidase - converts hypoxanthine to xanthine, and then to uric acid. •Allopurinol is substrate and inhibitor of xanthine oxidase; delays metabolism of other substrates; effective for treatment of gout.
  311. 311. Non-CYP Drug Oxidation • Flavin Monooxygenases – Family of enzymes that catalyze oxygenation of N, P, S – particularly formation of N-oxides; – Different FMO isoforms have been isolated from liver, lungs – Require molecular oxygen, NADPH, flavin adenosine dinucleotide (FAD)
  312. 312. Phase II or Conjugation Reaction • Glucuronic Acid Conjugation –most common • Ex: morphine, paracetamol, chloramphenicol • Conjugation with Glycine, Glutamine and other Amino Acids – used to conjugate carboxylic acids • ex: benzoic acid to hippuric acid • Glutathione or Mercapturic Acid Conjugation – an important pathway by which chemically reactive electrophilic compounds are detoxified; free radical scavenger
  313. 313. Phase II or Conjugation Reaction •Sulfate Conjugation •Acetylation – acetyl group is utilized that is supplied by the Acetyl CoA • ex: Hydralazine, isoniazid •Methylation – common among catecholamines (for their inactivation) • ex: COMT
  314. 314. Glucuronidation / Glucuronic Acid Conjugation 1. Readily available supply of d-glucuronic acid (from glucose) 2. Numerous functional groups that combine enzymatically with glucuronic acid 3. Glucuronyl moiety, polar hydroxyl groups which greatly increases water solubility when attached to the xenobiotics substrate.
  315. 315. Glucuronidation / Glucuronic Acid Conjugation • Enzyme: Uridine diphospho-glucuronyl transferase • Raw substance: Glucose-1-phosphate • Requires UTP to activate UDP-Glucose to UDPG • Multiple forms produced by alternate splicing at the UGT 1 locus of at least 7 different forms of exon 1 with remaining, and constant, region (exons 2-5).
  316. 316. GLUCURONIC ACID •Formation of ß-glucuronides involves two steps: • synthesis of an coactivated enzyme uridine-5’diphospho - glucoronic acid (UDPGA) • Transfer of the glucuronyl group from UDPGA to an appropriate substrate.
  317. 317. Sulfate Conjugation • Process occurs primarily with phenols (susceptible to sulfate formation), alcohols, aromatic amines, and N-hydroxy compounds; • ENZYME: Sulphonyltransferase/Sulfotransferase • ACTIVATED CONJUGATING INTERMEDIATE: 3’-phosphoadenosine-5’- phosphosulfate (PAPS)
  318. 318. Conjugation with glycine, glutamine, and other Amino Acids •Conjugates carboxylic acids particularly aromatic and arylaklyl acids. •Example: • Benzoic Acid to ________ • Salicylic acid to ________
  319. 319. Conjugation with GSH or Mercapturic acid • Important pathway for detoxifying chemically reactive electrophilic compounds. • Process involves enzymatic cleavage of two amino acid – glutamic acid and glycine • ENZYME: glutathione S-transferase using glutathione thiolate • Degradation of GSH is due to renal and hepatic microsomal enzymes • Example: Brompheniramine, Haloperidol, Diphenhydramine
  320. 320. Acetylation •May or may not result in more water soluble metabolites; Increases renal excretion •Acetyl group is supplied by high energy molecule Acetyl CoA •Constitutes a metabolic route for drugs containing primary amino groups, which includes the following: • Aromatic amines, Sulfonamides, Hydrazines, Hydrazides, Aliphatic amines
  321. 321. Acetylation •Derivatives formed from these amino functionalities are inactive and non- toxic. •Its primary function is the termination of pharmacological activity and detoxification •Less water solubility •Acetyl group used is acetyl-CoA •ENZYME: N-acetyltransferase
  322. 322. Methylation • Important but a minor pathway • Inactivation of physiologically active biogenic amines; • Does not convert metabolites to become more water soluble except when it creates a quaternary ammonium derivative; • Most of the products end up pharmacologically inactive. • ACTIVATED CONJUGATING INTERMEDIATE: s-adenosylmethionine (SAM) • ENZYME: Methyltransferase
  323. 323. Factors affecting Drug Metabolism • Age Differences • Species and Strain Differences • Hereditary or Genetic Factors • Sex Differences • Enzyme Induction/Inhibition • Environmental determinants • Others: • Dietary • Disease • Physiological factor (Pregnancy)
  324. 324. Age • Extremes of age are associated with disturbances in metabolism of drugs. • In pediatric age group • Premature infants, neonates, children and adolescents cannot be treated like small adults. • All these groups have special metabolic parameters. • Fetus: CYP3A sub-family only poor metabolism. • Neonates virtually no Phase-2 enzymes
  325. 325. Age • Hepatic biotransformation and enzyme activity is reduced in the early neonatal stages. • There is decreased biotransformation of drugs and increased plasma levels and prolonged half life. • Less developed excretory mechanisms. • Malnutrition in children can impair metabolism.
  326. 326. Age: Gray Baby Syndrome • Drug: _______toxicity leading to inadequate glucuronidation due to diminished glucuronyl transferase activity – Immature kidney exhibits inadequate renal excretion of unconjugated drug and glucuronide conjugate. • Elimination half life 26 hours in neonates • 4 hours in older children
  327. 327. Age: Elderly Patients • Patients > 65 years complex pharmacokinetic changes occur. • Decrease in liver size and liver blood flow • Activity of phase I pathways is reduced thus drugs predominantly metabolised by this path may show an exaggerated response. • eg. Diazepam as sedative • Irregular eating habits and vitamin deficiencies are associated with impaired metabolism
  328. 328. Age: Elderly Patients •Diminished enzyme induction •Drug-drug interactions are more common • Larger number of drugs being prescribed. • Both induction and inhibition are seen. •Renal excretion of drugs and metabolites is impaired
  329. 329. Sex Difference •Usually associated with sex hormones •Notable difference in metabolism of drugs like: • Alcohol • Benzodiazepines • Some anti-inflammatory • Propranolol oxidation M > F • Morphine • Erythromycin (N-demethylation) F > M
  330. 330. Pregnancy •In pregnancy there is a concern for fetus •Placenta high in CYP1A family if smoker. •Consequences to fetus or neonate: teratogenicity, carcinogenicity, hepatotoxicity •Can have profound induction in pregnancy. • e.g., may have to increase anticonvulsants.
  331. 331. Environmental Factors •Cigarette smoke leads to enzyme induction and increases the breakdown of drugs. •Exposure to industrial chemicals, pollutants also alters metabolism. •Clinical outcome: • Increase dose in smokers • Drugs with narrow safety margins should be given carefully.
  332. 332. Disease •Cardiac disease leads to decreased blood flow to liver and delayed metabolism. •Pulmonary disease may impair metabolism of certain drugs. •Thyroid disorders may lead to fast metabolism-hyperthyroidism or vice versa.
  333. 333. Genetic/Hereditary Factors •Pharmacogenetics/genomics as a discipline that explains why patient's response to drug therapy is different from another patient when both are being treated with the same drug for the same problem. •Provides an understanding of the outcomes of therapy.
  334. 334. Pharmacogenomics •Pharmacogenetics: is to use a patient's genetic profile to optimize drug therapy and minimize drug toxicity •Pharmacogenomics: identifying innovative drug targets and accounting for the effect that DNA sequence variations have on a drug's effectiveness.
  335. 335. Examples DRUG GENETIC VARIATION RESULT Codeine Defective CYP2D6 ; cannot convert codeine to morphine Decrease analgesia Phenytoin Defective CYP2C9; can result to over dosa Ataxia Confusion Warfarin Defective CYP2C9; decrease warfarin clearance Bleeding
  336. 336. Genetic/Hereditary Factors • Ethnicity has a role in determining how well a patient metabolizes drugs • Categorized as: Poor/ intermediate/ extensive and ultra-rapid metabolizers. • The incidence of toxicity or decreased efficacy depends on how the specific variant of the gene affects an enzyme, causing ????
  337. 337. Genetic/Hereditary Factors •Slow acetylators: Isoniazid SE peripheral neuropathy •Fast acetylators: low therapeutic level and hepatotoxicity
  338. 338. Predict the Drug-Drug/Food Interaction • Steroid based OCP and Rifampicin • Paracetamol and Ethanol • Cyclosporin and St. John’s Wort • Warfarin and Chloramphenicol • Terfenadine and Erythromycin, Ketoconazole, Grapefruit juice
  339. 339. FACTORS THAT INFLUENCE DRUG METABOLISM (Comprehensive Pharmacy Review, 8th ed.) • Chemical Structure • Genetic difference or polymorphism • Gender • Age • Circadian rhythms • Disease states • Nutritional status • Enzyme inducer/inhibitors • Route of drug administration • Dose
  340. 340. Inhibition vs. Induction Enzyme Inhibitor Enzyme Inducer Cimetidine Phenobarbital Ketoconazole Rifampicin Fluconazole Carbamazepine Miconazole Phenytoin Macrolides(except Azithromycin) Griseofulvin Fluoroquinolones(except Levofloxacin) Smoking Chronic alcoholism
  341. 341. Types of Enzyme Inhibition • Irreversible inhibition: the drugs reacts with the enzyme and forms a covalent bond. • Competitive inhibition: type of inhibitors that bind to the active site and compete with either the substrate or co- factor.
  342. 342. Types of Enzyme Inhibition • Uncompetitive inhibition: binds to enzyme-substrate complex in which its effect cannot be overcome by increasing the substrate concentration. • Allosteric inhibition: this type of inhibitors binds to a binding site different from the active site. They alter the shape of the enzymes such that the active site is no longer recognizable.
  343. 343. PACOP 2012 QUESTION • Which of the following drugs correctly produce such metabolites comparable to the activity of the parent compound? A. Oxidation of mercaptopurine B. Demethylation of morphine C. Deakylation of isoniazid D.Isomerization of retinoic acid
  344. 344. Excretion is Irreversible • The main route of excretion of a drug and its metabolites is through the _____________. • Enterohepatic circulation: the drug re- enters the intestinal tract from the liver through the bile duct, can be an important part of the agent’s distribution in the body and route of excretion.
  345. 345. • Renal excretion: • 3 processes: glomerular filtration  secretion  tubular reabsorption Excretion is Irreversible
  346. 346. • Drugs with high water/lipid partition coefficients are reabsorbed readily while those with low lipid/water partition coefficients are unable to diffuse back across the tubular membrane and are excreted in the urine unless reabsorbed by an active carrier system. • Altering the pH of the urine can result to termination of biological activity of weakly acidic and basic drugs Excretion is Irreversible
  347. 347. Types of Pharmacologic Action of the Drugs • Structural Non-specific Drugs ▫ Dependent on physical properties ▫ Drugs which do not depend its pharmacologic action to the chemical structure of the drug. ▫ Structurally non-specific action results from accumulation of a drug in some vital part of a cell with lipid characteristics. ▫ Examples: General anesthetics, hypnotics, few bactericidal compounds and insecticides.
  348. 348. • Structural Specific Drugs ▫ drugs in which the pharmacologic action directly dependent on its chemical structure; it attaches itself to a receptor in the biophase • Three prerequisites of the binding of drug to the receptor: (1) chemical reactivity; (2) presence of functional group; (3) electronic distribution; and (4) mirror-like image of the receptor. Types of Pharmacologic Action of the Drugs
  349. 349. Kinds of Routes: • Oral Route • Per-oral Route • Rectal Route • Parenteral Route ▫ ID ▫ SC/SQ ▫ IM ▫ IV ▫ Epicutaneous
  350. 350. Drug – Receptor Interactions • Lock and Key Concept ▫ Lock  Receptor surface ▫ Key  Drug or Ligand Receptor Drug
  351. 351. Drug-Receptor Theories •Hypothesis of Clark ▫ “ The Pharmacologic effect of the drug depends on the percentage of the receptors occupied” ▫ If receptors are occupied, maximum effect is obtained. ▫ Chemical binding follow the Law of Mass Action.
  352. 352. •Hypothesis of Paton • “ Effectiveness of a drug does not depend on the actual occupation of the receptor but by obtaining proper stimulus” • This is also known as the Rate Theory. Drug-Receptor Theories
  353. 353. • Hypothesis of Ariens and Stephenson • “ Effectiveness of a drug lasts as long as the receptor is occupied. Many substance possess different effect , some have high affinity for the receptor, some have low affinity and some are not effective, and those ineffective substances block or inhibit the receptor.” • It is also called Occupancy Theory. Drug-Receptor Theories
  354. 354. Other Drug Receptor Theories • Activation aggregation theory: receptors are always in dynamic equilibrium between active and inactive states. • Agonist function by shifting the equilibrium toward the activated state, whereas antagonists prevent the activated state.
  355. 355. Other Drug Receptor Theories •Induced-fit theory of enzyme- substrate interaction • suggest that as the drug approaches the receptor, a conformational change occurs in the receptor to allow effective binding.
  356. 356. • Macromolecular perturbation theory ▫ suggest that two types of conformational changes exist and the rate of their existence determines the observed biological response Other Drug Receptor Theories
  357. 357. What is QSAR? • Quantitative Structure Activity Relationship -or- • Qualitative Structure Activity Relationship?
  358. 358. Quantitative Structure- Activity Relationships (QSAR) • Attempts to identify and quantitate physicochemical properties of a drug in relation to its biological activity or binding. • Studies hydrophobic, electronic, and steric properties--either whole molecule or pieces.
  359. 359. • Advantage: fewer compounds may need to be made. • However, if compound does not “fit” the equation, then chemist knows they need to modify the equation. Quantitative Structure- Activity Relationships (QSAR)
  360. 360. PACOP 2012 QUESTION • Which of the following statement is/are true regarding the biologic activity of some stereochemical isomers? A. Only the l-isomer of ascorbic acid has anti-scurvy activity B. Only the d-isomer of the a and b-glucose show high affinity for the human RBC sugar transfer system C. Only the l-isomer of a-methyldopa has hypotensive property D. Only the l-isomer always has high anti-bacterial activity
  361. 361. Steric Features and Pharmacologic Activity •Stereochemistry: Space arrangement of the atoms or three- dimensional structure of the molecule. 378
  362. 362. I. Optical and Geometric isomerism and Pharmacological activity • Optical isomers are compounds that contain at least one chiral carbon atom or are compounds that differ only in their ability to rotate the polarized light. 379 Steric Features and Pharmacologic Activity
  363. 363. 380 Enantiomers (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. CH3 OH HH3C CH3 H CH3 OH 2-Hydroxybutane enantiomers (mirror images can not superimposed) Steric Features and Pharmacologic Activity
  364. 364. 381 Geometric isomerism (cis- trans isomerism). Steric Features and Pharmacologic Activity
  365. 365. 382 N + HH H H OAc (CH3)3 N + HH OAc H H (CH3)3 Trans Gauche Conformations of acetylcholine • Conformational isomerism is the non- identical space arrangement of atoms in a molecule, resulting from rotation about one or more single bonds. For example, the trans(antiperiplanar) conformation of acetylcholine binds to the muscarinic receptor, where as the gauche conformation binds to the nicotinic receptor. Steric Features and Pharmacologic Activity
  366. 366. Isosterism, Bio-isosterism and Pharmacological activity Isosterism: Any two ions or molecules having an identical number and arrangement of electrons; the term is used to describe the selection of structural components – steric, electronic and solubility characteristics that makes them interchangeable in drugs of the same pharmacological class.
  367. 367. 384 Bioisosterism is the procedure of the synthesis of structural analogues of a lead compound by substitution of an atom or a group of atoms in the parent compound for another with similar electronic and steric characteristics. Isosterism, Bio-isosterism and Pharmacological activity
  368. 368. 385 Bioisosteres are functional groups which have similar spatial and electronic character, but they retain the activity of the parent. Isosterism, Bio-isosterism and Pharmacological activity
  369. 369. 386 Friedman defined bio-isosterism as- the phenomenon by which compounds usually fit the broadest definition of isosteres and possess the same type of biological activity. E.g. (Antihistamine; A; B and C) CHO CH2CH2 N CHO CH2CH2 N CH2CH3 CH2CH3 CHO CH2CH2 N CH3 CH3 A B C Compound A has twice the activity of C, and many times greater than B Isosterism, Bio-isosterism and Pharmacological activity
  370. 370. • Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties. • Bioisosterism is a lead modification approach that has been shown to be useful to attenuate: •Toxicity • Modify the activity of a lead • May have a significant role in the alteration of metabolism of the lead Isosterism, Bio-isosterism and Pharmacological activity
  371. 371.  
  372. 372. Joseph Lister: “sterile surgery”. He used _________ or _____________ as antiseptics for use in surgery and post- traumatic infections or “ward fever”. Paul Ehrlich: worked on antibacterial dyes, organo-arsenicals (tx for syphilis) and the so-called “magic bullets” Phenol Carbolic acid
  373. 373. Which of the following antibacterial agents acts by inhibiting the metabolism of microbial organisms but not of the hosts? A. Sulfonamides B. Polymyxins C. Penicillins D. Rifamycins E. Nalidixic acid
  374. 374. Selective toxicity oA property of a certain medicinal agent to kill one type of pathogenic microorganisms without harming the host’s cell.
  375. 375. Anti-infectives: are substances that destroys or kill microorganisms that causes infection. Germicides: are compounds that is used locally to kill microorganism. aka “local anti-infective agents” Please refer to table 6.1, page 180 for other terminologies.
  376. 376. Antiseptic: are compounds that kill (- cidal) or prevent the growth (-static) of microorganisms when applied to living tissues. Disinfectant: agents that prevents the transmission of infection by the destruction of pathogenic microorganisms when applied to inanimate objects. Please refer to page 180 for the ideal properties/characteristics of antiseptic and disinfectant.
  377. 377. Phenol coefficient: is the ratio of a dilution of a given test disinfectant to the dilution of phenol required to kill a given strain of __________. A. Pseudomonas aeruginosa B. Mycobacterium leprae C. Bacillus subtilis D. Salmonella typhi
  378. 378. Energy Metabolism Cytoplasm Bacterial pores
  379. 379. SARs of alcohol  1° > 2° > 3°  Length of 1° increases what will be the effect?  The antibacterial activity of alcohol increases with increasing molecular weight until the ___ carbon only.  Branching also decreases solubility.  Straight > Branched alcohol WHY???  The organism used to test the antibacterial property is ____________________.Staphylococcus aureus 8th
  380. 380. Which among the list is the most water soluble? A. Methanol B. Ethanol C. Propanol D. Butanol E. Pentanol
  381. 381. Alcohol(95%): alcohol in pharmacy will always pertain to ETHANOL, is a clear, colorless, volatile liquid with a burning taste and a characteristic odor.  Synonyms: ___________, __________ refer to pg. 181 for other names  Fermentation product of grain and other carbohydrate containing sources.  Most widely used recreational drug.  Undergoes a series of oxidation – reduction reactions in vivo. Ethyl alcohol wine spirit
  382. 382. Oxidation of Alcohols
  383. 383. Denatured Alcohol: ethanol that has been rendered “unfit for use” in intoxicating beverages by the addition of other substances. Completely Denatured Alcohol: a denatured alcohol that contains methanol and benzene that is unsuitable for external and internal use.
  384. 384. Specially Denatured Alcohol: ethanol that is treated with one or more substance to be used in tinctures, MW, lotions and extraction purposes. Dehydrated Ethanol: “Absolute ethanol” contains NLT 99% w/w, prepared by azeotropic distillation of ethanol-benzene mixture.  Used in pain in carcinoma, neuralgias and as chemical reagent or solvent.
  385. 385. Isopropyl alcohol aka ____________ or ____________ with slightly bitter taste, 91% v/v of isopropanol. Primary use is to cleanse the skin and disinfect surgical apparatus/instruments. Prepared by hydration of propylene with sulfuric acid as catalyst. Azeotropic isopropyl alcohol, USP: used in gauze pads. 2-propanol propan-2-ol
  386. 386. Benzyl alcohol: possess local anesthetic property.
  387. 387.  Antiseptic  Preservative  Mild counterirritant  Solvent  Astringent  Rubefacient  Mild local anesthetic  Analgesic in neuralgias  Mild sedative  Weak vasodilator  Carminative External use Rubbing alcohol Internal use
  388. 388. Ethylene oxide (C2H4O): used to sterilize temperature sensitive medical equipment and certain pharmaceuticals that cannot be autoclaved. Commercial product: Oxirane®, Carboxide® (10% E.O and 90% CO2) Non-selective alkylating agent therefore: _____________
  389. 389. Formaldehyde, USP (Formol, formalin): contains NLT 37% w/v of HCHO with methanol (WHY methanol is added?). Miscible with water and alcohol, cloudy at RT. Use/s: Embalming agent, deodorant, antiseptic; gas preparation is disinfectant for rooms, clothes and instruments.
  390. 390. Glutaraldehyde Disinfectant Solution (Cidex) aka Glutarol, used as sterilizing solution for equipment and instruments that cannot be autoclaved.
  391. 391. SARs of phenol: Substitution with alkyl, aryl, and halogen in ______ increases bactericidal properties. Presence of straight chain alkyl groups enhances bactericidal activity more than branched groups. Aklylated phenols and resorcinol are less toxic than parent compounds while retaining bactericidal properties.
  392. 392. MOA of phenol:  Acts on cell membrane and inactivates intracytoplasmic enzymes forming unstable complexes; the lipophilic part of the molecule is trapped by the membrane phospholipids  Phenols denature bacterial proteins at low concentrations; lysis of bacterial cell membrane occurs at higher concentration.
  393. 393. Phenol, USP: introduced by Joseph Lister (1867) as surgical alcoholic antiseptic. Used as the standard to which most germicides are compared. It is a colorless to pale-pink crystalline with characteristic “medicinal odor”. A general “protoplasmic poison” Phenolated calamine lotion is used as __________. Phenol-glycerin use ________.
  394. 394. Liquefied phenol: phenol with 10% water.  Use: pharmaceutical aid. p-chlorophenol: Used in combination with camphor in liquid petrolatum  Use: used externally as antiseptic and anti-irritant. p-chloro-m-xylenol (PC-MX, Metasep): nonirritating antiseptic with broad spectrum antibacterial and anti-fungal properties.  Available as shampoo which is used for the treatment of fungal infection.
  395. 395. Hexachlorophene (Gamophen, Surgicon, pHisoHex):a bisphenolic, more potent than monophenolic, easily absorbed onto skin and even sebaceous glands. Uses: 2%-3% in soaps, detergent creams, lotions and shampoo (antiseptic) Side effects: cause neurologic toxicity in infants and in burn patients.
  396. 396. Cresol, NF has a characteristic creosote odor; Obtained from coal tar or petroleum by alkaline extraction into aqueous medium, acidification and fractional distillation. Use/s: antiseptic and disinfectant Disadvantage: unpleasant odor
  397. 397. Chlorocresol (4-chloro-3-methyl- phenol): a colorless crystal and used as preservative. Thymol (isopropyl m-cresol) antifungal for the treatment of Tinea capitis, Tinea corpus. Eugenol (4-allyl-2-methylphenol): obtained from clove, a pale yellow liquid with strong aroma and pungent taste used as local anesthetic and antiseptic.
  398. 398. Resorcinol (m-dihydroxybenzene, resorcin): a white needle like crystals or amorphous powder Uses: weak antiseptic, keratolytic agent Hexylresorcinol (4-allyl-2- methylphenol) Cristoids, Caprokol: white crystals with faint phenolic odor and has astringent taste (numbness) Uses: Antiseptic, local anesthetic, surfactant
  399. 399. SARs: good and effective against anaerobic microorganism and in cleaning contaminated wounds. MOA: depend upon liberation of oxygen (peroxide) in the tissues and their ability to denature proteins (permanganates).
  400. 400. Carbamide peroxide Topical Solution (Gly-Oxide): Releases hydrogen peroxide when mixed with water. Uses: Disinfectant antiseptic; effective in treating oral ulcerations
  401. 401. Hydrous Benzoyl Peroxide (Oxy-5 and 10, Vamoxide, Panoxyl) explosive (pure) addition of 30% water to make it safer. Uses: at 5 to 10% concentration is as keratolytic, keratogenic and treatment of acne caused by propionic bacterium acnes (an anaerobic). MOA: induce proliferation of epithelial cells leading to sloughing and repair
  402. 402. Elemental Iodine: oldest and one of the most effective and useful germicide. Iodophors: complexes of iodine with non-ionic and cationic surfactants while retaining the germicidal property and reducing the volatility and irritant property of iodine
  403. 403. MOA: Protein inactivation by iodination of phenylalanyl and tyrosyl residues; oxidation of –SH groups Lugol’s solution is ____________ Iodine solution is ____________ Iodine tincture is ____________
  404. 404. Povidone – Iodine (Betadine®): Complex of iodine with PVP Betadine is ___% of iodine The complex is extremely water soluble and release iodine slowly, non-toxic, non-volatile, and non- staining to the skin or wounds.
  405. 405. Chlorine and its products are used mainly as water disinfectant. MOA: Chlorination (oxidation) of amide nitrogen (peptide bond) atoms in protein and oxidation of sulfhydryl.
  406. 406. Halazone (p- dichlorosulfamoylbenzoic acid): a white crystalline, photosensitive compound with faint chlorine odor. Use: Sodium salt is water disinfectant (drinking water)
  407. 407. Chloroazodin (N,N- dichlorodicarbonamidine, Azochloramid®): Uses: dilute solution as disinfectant for wounds, packaging of dental caries, and for lavage and irrigation. Glyceryltriacetate salt is for wound dressing.
  408. 408. Oxychlorosene Sodium complex of the sodium salt of dodecylbenzenesulfonic acid and HClO; combines germicidal properties of HOCl with the emulsifying, wetting and keratolytic actions of anionic detergent.
  409. 409.  Quaternary ammonium compounds that ionize in water and exhibit surface active properties.  Ends on “-onium or –inium”, water-soluble, non-staining, non-corrosive, manifest low toxicity.  Structural moieties:  Cationic head group: has high affinity for water  Long HC tail: affinity for lipids and non- polar solvents (G+ and G-)

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