ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014) ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014) Presentation Transcript

  • Refresher Course on Organic Chemistry and Organic Medicinal Chemistry Mr. Jan Dominique R. Lapig, RPh. April – May 2014
  • Part I: General Chemistry
  • 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.
  • 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)
  • 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.
  • Classification of Matter
  • 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
  • Separation of Mixtures Mixtures can be separated by physical means. –Filtration –Chromatography –Distillation Classification of Matter
  • Separation of Mixtures Classification of Matter
  • 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
  • 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
  • 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
  • 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.
  • 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
  • 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
  • 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
  • Physical and Chemical Changes Properties of Matter
  • Physical Properties of Drug Molecule • Physical States: –Amorphous solid –Crystalline solid –Hygroscopic solid –Liquid –Gas
  • 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
  • Physical Properties of Drug Molecule • Boiling point: temperature at which the vapor pressure of the liquid is equal to the atmospheric pressure
  • 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.
  • 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
  • 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
  • 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
  • Acid-base properties and pH
  • 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
  • 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.
  • 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?
  • 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+]
  • 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?
  • 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-]
  • 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.
  • 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
  • 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
  • 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
  • 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.
  • Units of Measurement SI Units
  • Units of Measurement SI Units
  • Temperature Units of Measurement
  • 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
  • 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
  • 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
  • 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
  •  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
  • 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
  • Precision and Accuracy Uncertainty in Measurement
  • 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.
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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)
  • 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.
  • 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.
  • 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.
  • 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.
  • Remember the following: •Neils Bohr
  • 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.
  • 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
  • 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.
  • Remember the following:
  • 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
  • Practice Set • Given: Boron, Nitrogen, Phosphorus • Find the following: ▫ Electronic configuration ▫ Orbital diagram ▫ Core configuration ▫ Graphical diagram ▫ Valence number
  • Part II: Organic Chemistry
  • INORGANIC CHEMISTRY  is the branch of chemistry concerned with the properties and behavior of inorganic compounds. Inorganic vs. Organic Chemistry
  • The Periodic Table
  • ORGANIC CHEMISTRY  is the branch of chemistry which deals with carbon- containing compounds. Inorganic vs. Organic Chemistry
  • 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).
  • 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
  • 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
  • Common Terminologies in Organic Chemistry refer to your notes 
  • Carbon: The Chemical Basis for Life  From the Latin word “carbo” meaning charcoal.  Group __ element  IUPAC classification: Group __ element  Symbol: ___  Atomic no.: ___
  •  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
  • Allotropes of Carbon
  •  Fullerene  antioxidant  Amorphous Carbon  adsorbent Allotropes of Carbon
  •  Crystal Structure: Hexagonal  Electronic configuration Carbon Facts
  • 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.
  • HYBRIDIZATION
  • 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.
  •  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
  • Orbitals
  • s-orbital p-orbitals bond side ways overlap end to end overlap of orbitals leads to σ -bond σ -bond HYBRIDIZATION
  • Types of Carbon Hybrid Orbitals  sp3 hybrid or tetrahedral hybrid  sp2 hybrid or trigonal planar hybrid  sp hybrid or linear hybrid
  • Types of Carbon Hybrid Orbitals  sp3d hybrid  sp3d2 hybrid
  • 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
  • 109.50 sp3 hybridized carbon 4 equivalent C-H bonds (s-bonds) All purely single bonds are called s-bonds Methane is Tetrahedral
  • sp2 hybrid or Trigonal hybrid  *C6 1s2 2s1 2px1 2py1 2pz1 pure AO  (2sp2)1(2sp2)1 (2sp2)1 2pz1 hybrid AO
  • sp hybrid or Linear hybrid  *C6 1s2 2s1 2px1 2py1 2pz1 pure AO  (2sp)1(2sp)1 2py1 2pz1 hybrid AO
  • Questions on Hybridization
  • 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
  •  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
  • Identify the Hybridization CH3CH2CH=CHCH2CCH
  • Identify the Hybridization
  • Identify the Hybridization
  • Identify the Hybridization
  • 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.
  •  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:
  •  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:
  • Hydrocarbon and derivatives
  • 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.
  • Hydrocarbon Derivatives • An almost unlimited number of carbon compounds can be formed by the addition of a functional group to a hydrocarbon.
  • Type or General Formula Class Type formula Alkane CnH2n+2 Alkene CnH2n Alkyne CnH2n-2 Cycloalkane CnH2n Cycloalkene CnH2n-2 Cycloalkyne CnH2n-4
  • Cyclopropane Cyclohexane Cyclobutane Cyclooctane
  • 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
  • Who discovered the structure of benzene? Friedrich August Kekule
  • Phenol Ar-OH Ether R-O-R Aldehyde R- CHO Ketone R-CO-R Type or General Formula
  • 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
  • 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
  • Nitroso R-N = O Nitrile (cyanide) R-C  N Imine Imide Type or General Formula
  • Diazo Hydrazino R-NHNH2 Mercaptan (thiol) R-SH Thioether R-S-R Enol Type or General Formula
  • 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
  • What is the type formula for ethers? A. RH B. RX C. ROR D. RCHO E. RCOOR PACOP QUESTION
  • The compound with the formula CH3CH2COCH2CH3 is a/an: A. Ketone B. Aldehyde C. Carboxylic acid D. Ether E. Ester PACOP QUESTION
  • The structure shown below is: C C C C C C H H H H HH =
  • Naphthalene Anthracene Phenanthrene The structure shown below is:
  • Isomers • compounds having the same molecular formula but different structural formulas.
  • 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.
  • Types of Structural Isomers • Chain isomers or skeletal isomers • Positional isomers • Functional isomers ▫ Tautomers
  • • Chain/Skeletal isomers ▫ Compounds that differ in the arrangement of carbons. Types of Structural Isomers
  • • Positional isomers ▫ Differ in the position of a non carbon group. Types of Structural Isomers
  • • Functional Isomer ▫ Differ in the functional group. Types of Structural Isomers
  • •2-pentanol and 3-pentanol are: A. Functional isomers B. Positional isomers C. Chain isomers D.Optical isomers E. Stereoisomers PACOP QUESTION
  • •2 - pentanol ▫ CH3CHOHCH2CH2CH3 •3 - pentanol ▫ CH3CH2CHOHCH2CH3 Answers:
  • 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.
  • 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.
  • • Diastereomers ▫ Stereoisomers that are non – superimposable and non – mirror images of each other. Types of Configurational Isomers
  • Enantiomer vs. Diastereomers
  • • 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
  • trans vs. cis isomers
  • •Enantiomers differ from one another in: A.Spatial configuration B.Rational formula C.Ion-pair formation D.Photoelectric effect PACOP QUESTION
  • R vs. S Configuration Cahn-Ingold-Prelog system Determines R or S designation of enantiomers
  • Chiral or Asymmetric Center • Chiral or Asymmetric Center ▫ a molecule which contains a carbon to which four different groups are attached.
  • Identify which is the Chiral carbon
  • What type of isomerism is this?
  • Tautomers • Isomers that differ from each other in the position of hydrogen atom and double bond.
  • •Propanone and 1 – propen-1-ol are considered; A. Positional isomers B. Configurational isomers C. Tautomers D.Enantiomers E. Chain isomers PACOP QUESTION
  • Tautomers
  • • They are diastereomers that differ only in the position of moieties at the first carbon atom. Anomers
  • Meso Compound • one whose molecules are superimposable on their mirror images, even though they contain chiral centers.
  • Racemic Mixture • mixture of equimolar concentration of enantiomers in a solution.
  • IUPAC System Nomenclature •STEP 1: Name the Parent name. • Select the longest continuous chain. Hexane
  • •STEP 2: Number the Cs in the chain, from either end, such that the substituent are given the lowest #s possible. IUPAC System Nomenclature
  • • 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
  • • 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
  • 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
  • Guide for Organic Nomenclature:
  • 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
  • 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 –
  • • 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
  • • 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
  • • What is the type formula of the chemical methoxyethane? A. RCHO B. RCOOH C. RCOOR D. RCOR E. ROR PACOP QUESTION
  • Name the following:
  • Mechanism of Reaction: the detailed course of overall reaction. • Sequence of steps • Details of electron movement • Bond breaking • Bond making • Timing
  • • 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.
  • Types of Bond Cleavage • Homolytic Cleavage ▫ Characterized by homolytic fission of bonds and the formation of free radicals.
  • • Heterocyclic Cleavage ▫ Characterized by heterocyclic fission and the formation of charged species. Types of Bond Cleavage
  • Types of Reagents •1. Nucleophiles (Nu:) ▫ electron-rich species ▫ electron pair donor ▫ attack positions with + charge or low electron density
  • •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
  • Types of Reaction Intermediates
  • Types of Organic Reactions • Substitution reaction • Addition reaction • Elimination reaction • Rearrangement reaction • Oxidation • Reduction
  • Substitution Reaction
  • Addition Reaction
  • Elimination Reactions
  • Rearrangement Reaction
  • Oxidation • increase in oxygen • Increase in electron • decrease in hydrogen
  • Reduction • increase in hydrogen • decrease in electron • decrease in oxygen
  • Atomic Bonds 1. Ionic bonding 2. Covalent bonding 3. Hydrogen bonding or bridging) 4. Van der Waals (London forces)
  • Ionic Bonding ▫ electrostatic interaction resulting from the transfer of an electron during the compound formation. Atomic Bonds
  • Covalent Bonding ▫ is the attractive force that exists between two chemicals entities due to their sharing a pair of electrons. Atomic Bonds
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • •Upon storage, alcohols are stable •In vivo, alcohols may undergo ▫ Oxidation ▫ Glucoronidation ▫ Sulfation Alcohols
  • 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
  • • 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
  • Important Alcohols and Phenols • Methanol • Ethanol • Isopropyl alcohol • Cholesterol • Glycerol • Ethylene glycol • Phenol • Cresol • Resorcinol • Hexylresorcinol • Menthol • Geraniol • Glucose
  • 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
  • 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
  • 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
  • Important Aldehydes • Formaldehyde • Acetaldehyde • Chloral hydrate • Benzaldehyde • Cinnamaldehyde • Vanillin • Citral
  • 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
  • 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
  • • 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
  • • 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
  • Carboxylic acids • Lipid soluble ▫ LMW carboxylic acids are water soluble (Na, K salts) • Common reactions are: ▫ Salt formation with bases ▫ Esterification ▫ Decarboxylation
  • • On the shelf, carboxylic acids are very stable • In vivo, carboxylic acids undergo ▫ Conjugation with glucoronic acid, glycine and glutamine ▫ Beta oxidation Carboxylic acids
  • Important Carboxylic acids • Salicylic acid • Citric acid • Lactic acid • Tartaric acid • Benzoic acid • ASA • PABA
  • 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
  • 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
  • Important Amides •Acetanilide •Niacinamide or nicotinamide •Sulfanilamide
  • Part III: Organic Medicinal Chemistry Mr. Jan Dominique R. Lapig, RPh April – May 2014
  • Medicinal Chemistry “…let’s make a change on an existing compound or synthesize a new structure and see what happens…”
  • What is Medicinal Chemistry? • Medicinal Chemistry is a chemistry-based discipline, involving the aspects of biological, medical and pharmaceutical sciences.
  • What is Medicinal Chemistry? • Medicinal Chemistry devoted to the discovery and development of new agents for treating diseases. - Wilson and Gisvold’s 12th ed.
  • Synthetic Chemistry • involves changes designed to transform a starting substance with a particular set of properties.
  • 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
  • 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
  • • 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
  • •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
  • 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.
  • 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).
  • 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”
  • 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
  • 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
  • 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
  • • 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:
  • • 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:
  • •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:
  • •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:
  • 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
  • • 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
  • • 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
  • ▫ 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
  • Drug Development
  • Life Cycle for new drug :
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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
  • 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.
  • Historical Timeline: Elixir 1906 1937 No Regulatory control for Drug safety Sulfanilamide disaster Federal Food and Drug Act passed 1938 1961 Thalidomide crisis
  • 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.
  • 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
  • • 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:
  • Helpful mnemonics
  • •Biotechnology techniques a. Recombinant DNA b. Mutagenesis- site directed that fuse cell lines Discovery & Development of Organic Medicinal Chemicals:
  • 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
  • •ANIMAL SOURCES: Glandular products from animals are used, such as insulin and thyroid. Sources of Drugs
  • • 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
  • • 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
  • 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.
  • 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:
  • 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:
  • 1. CHEMICALLY DERIVED STEMS  PREFIX cef- (cephalosphorins) cefotetan, cefixime  INFIX -nab- (cannabinols) dronabinol, tinabinol  SUFFIX –azoles (antifungal imidazole) ketoconazole, fluconazole, itraconazole. Naming of Drugs
  • 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
  • 3.COMBINATION STEMS e.g. *–olol (beta blockers): timolol, atenolol, metoprolol *–profen (ibuprofen type; anti- inflammatory/analgesic agents): ibuprofen, ketoprofen Naming of Drugs
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • •Site-specific prodrugs: where carrier acts as transporter of the active drug to a specific targeted site. Prodrug
  • 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 _______.
  • 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 _______.
  • • 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
  • 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)
  • 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
  • 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
  • BIOLOGICAL EFFECT OF A DRUG • result of an interaction between the drug substance and functionally important cell receptors or enzyme systems.
  • 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.
  • 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.
  • • 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:
  • Physicochemical Properties • Polarity • Acidity/Basicity • Dissolution • Particle size and Surface Are • Salt formation • Polymorphism • Chirality • Hydrates • Complex formation • Viscosity
  • 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
  • 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
  • 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)
  • 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
  • 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
  • Solubility Prediction Soluble Insoluble
  • 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).
  • 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.
  • 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
  • Consider the following: •Indomethacin pKa = 4.5 well absorbed in ____________. •Ephedrine pKa = 9.6 well absorbed in _____________.
  • Forces of Attraction • Van der Waals • Dipole-dipole bonding • Ionic bonding • Ion-dipole binding • Covalent bond • Reinforce ionic • Hydrogen bond • Hydrophobic bond
  • Physicochemical Properties • Polarity • Acidity/Basicity • Dissolution • Particle size and Surface Area • Salt formation • Polymorphism • Chirality • Hydrates • Complex formation • Viscosity
  • 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.
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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
  • Tissue Depot • The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots. • Barbiturates activity
  • Importance of Drug Metabolism • The basic premise: • Lipophillic Drugs  Hydrophillic Metabolites (Not Excreted) (Excreted) • Generally pharmacologically inactive and • Non-toxic metabolites
  • 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.
  • 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 ____________.
  • 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.
  • Importance of Drug Metabolism •Termination of Drug Action • Bioinactivation • Detoxification • Elimination
  • Importance of Drug Metabolism •Bioinactivation
  • Importance of Drug Metabolism •Detoxification
  • Importance of Drug Metabolism •Elimination
  • Importance of Drug Metabolism •Bioactivation • Active Metabolites • Prodrug • Toxification
  • Importance of Drug Metabolism •Active Metabolites
  • Importance of Drug Metabolism •Prodrug
  • 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
  • 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.
  • 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.
  • 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
  • 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
  • Question •What will happened to drugs that are resistant to drug-metabolizing enzymes?
  • •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
  • Mixed function oxidases or Monooxygenases Capital Letter Arabic Number family Capital Letter subfamily system Arabic Number enzyme
  • 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 ___________
  • 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 ________
  • 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.
  • Reduction Clonazepam • Nitroreductase • Bacterial reductase • Aldo-keto reductase • NADPH cytochrome-c- reductase ENZYMES
  • 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
  • Hydrolysis Procainamide • Esterases • Amidases • Phosphatase • Sulphatases • Expoxide hydroxylase ENZYMES
  • 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.
  • 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
  • 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.
  • 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)
  • 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
  • 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
  • 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.
  • 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).
  • 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.
  • 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)
  • Conjugation with glycine, glutamine, and other Amino Acids •Conjugates carboxylic acids particularly aromatic and arylaklyl acids. •Example: • Benzoic Acid to ________ • Salicylic acid to ________
  • 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
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 ????
  • Genetic/Hereditary Factors •Slow acetylators: Isoniazid SE peripheral neuropathy •Fast acetylators: low therapeutic level and hepatotoxicity
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • • Renal excretion: • 3 processes: glomerular filtration  secretion  tubular reabsorption Excretion is Irreversible
  • • 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
  • 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.
  • • 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
  • Kinds of Routes: • Oral Route • Per-oral Route • Rectal Route • Parenteral Route ▫ ID ▫ SC/SQ ▫ IM ▫ IV ▫ Epicutaneous
  • Drug – Receptor Interactions • Lock and Key Concept ▫ Lock  Receptor surface ▫ Key  Drug or Ligand Receptor Drug
  • 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.
  • •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
  • • 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
  • 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.
  • 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.
  • • 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
  • What is QSAR? • Quantitative Structure Activity Relationship -or- • Qualitative Structure Activity Relationship?
  • 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.
  • • 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)
  • 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
  • Steric Features and Pharmacologic Activity •Stereochemistry: Space arrangement of the atoms or three- dimensional structure of the molecule. 378
  • 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
  • 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
  • 381 Geometric isomerism (cis- trans isomerism). Steric Features and Pharmacologic Activity
  • 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
  • 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.
  • 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
  • 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
  • 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
  • • 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
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  • 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
  • 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
  • Selective toxicity oA property of a certain medicinal agent to kill one type of pathogenic microorganisms without harming the host’s cell.
  • 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.
  • 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.
  • 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
  • Energy Metabolism Cytoplasm Bacterial pores
  • 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
  • Which among the list is the most water soluble? A. Methanol B. Ethanol C. Propanol D. Butanol E. Pentanol
  • 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
  • Oxidation of Alcohols
  • 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.
  • 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.
  • 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
  • Benzyl alcohol: possess local anesthetic property.
  •  Antiseptic  Preservative  Mild counterirritant  Solvent  Astringent  Rubefacient  Mild local anesthetic  Analgesic in neuralgias  Mild sedative  Weak vasodilator  Carminative External use Rubbing alcohol Internal use
  • 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: _____________
  • 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.
  • Glutaraldehyde Disinfectant Solution (Cidex) aka Glutarol, used as sterilizing solution for equipment and instruments that cannot be autoclaved.
  • 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.
  • 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.
  • 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 ________.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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).
  • Carbamide peroxide Topical Solution (Gly-Oxide): Releases hydrogen peroxide when mixed with water. Uses: Disinfectant antiseptic; effective in treating oral ulcerations
  • 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
  • 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
  • MOA: Protein inactivation by iodination of phenylalanyl and tyrosyl residues; oxidation of –SH groups Lugol’s solution is ____________ Iodine solution is ____________ Iodine tincture is ____________
  • 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.
  • 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.
  • Halazone (p- dichlorosulfamoylbenzoic acid): a white crystalline, photosensitive compound with faint chlorine odor. Use: Sodium salt is water disinfectant (drinking water)
  • 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.
  • 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.
  •  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-)
  •  Has bactericidal action against a broad spectrum of G+ and G- bacteria, fungi and protozoa.  MOA:  lower down the interfacial tension: HOW???  dissolution into the microbial CM  destabilization/interference of the enzyme system  cell lysis  Please refer to page 187 for the advantages and disadvantages of cationic surfactants.
  • Benzalkonium Chloride (Alkylbenzyldimethylammonium chloride, Zephiran®) Uses: Detergent, emulsifier, wetting agent Antiseptic for skin and mucous membrane Irrigation solution Storage of surgical instruments
  • Methylbenzethonium Chloride (Diaparene®): used to control diaper rash caused by bacterium ammoniagenes which liberates ammonia in decomposed urine. A general antiseptic
  • Benzethonium Chloride (Phemerol chloride); is a colorless crystalline powder that is soluble in water, alcohol, and most organic solvents. Uses: Similar to Benzalkonium chloride
  • Cetylpyridinium Chloride (1- hexadecylpyridinium chloride, Ceepryn®) Uses: General antiseptic for skin, laceration, irrigation and available as throat lozenges and MW
  • Chlorhexidine Gluconate (Hibiclens®); most effective of a series of antibacterial biguanides, broad spectrum antibacterial activity (inactive against acid fast bacterial, spores and viruses). Uses: Antiseptic topically
  • Cationic dyes are active against gram + microorganisms and inactivating fungi; G- are resistant Forms colorless leucobase under alkaline condition Useful dyes (present) Gentian violet Basic fuchscin Methylene blue Triphenylmethane dye Thiazine dye
  • Gentian Violet (hexamethyl-p-rosaniline chloride, Genepax®): aka crystal violet, methyl violet, methylrosaniline chloride  Available as green powder or green flakes with metallic sheen Uses:  Available as vaginal suppository or _______ for the treatment for yeast infections.  1-3% solution for the treatment of ringworm and yeast infection.  Orally as an anthelmintic for threadworm and pinworm.
  • Basic fuchsin: mixture of chlorides of rosaniline and p- rosaniline; a green crystalline powder with a mettallic apperance Component of Carbol-fuchsin solution (Castellani’s paint), treatment of fungal infections like ringworm and athlete’s foot.
  • Methylene blue (Urised®): dark green powder with a metallic appearance; can cause methemoglobinemia; can tint the urine and stool ________ Uses: Has weak antiseptic properties (useful for the treatment of cystitis and urethritis) antidote for cyanide and nitrate poisoning
  • Elemental Mercury: local anti-infective and treatment of syphilis  Two Classes of Organomercurials  Compounds with at least one carbon-mercury bond that does not ionize readily  Compounds with mercury bonded to heteroatoms  SAR: organic moieties increase lipid solubility, render the compound bacteriostatic  MOA: reacts with the –SH of enzymes and other proteins by forming R-S-Hg-R’
  • Nitromersol (Methaphen®) MOA: formation of covalent compounds Use: antiseptic for skin and eye infection Thimerosal: previous active composition of merthiolate or “gamot na pula” is a cream colored, water-soluble powder, non-staining and non-irritating to tissues. Weakly bacteriostatic agent Merbromin: mercurochrom, red- orange
  • Prevents contamination Ideal characteristics of preservatives: Effective at low concentration against all possible microorganims Non toxic Compatible with other ingredients Stable for the shelf life of the products
  •  Esters of p-hydroxybenzoic acid “PARABENS”: useful antifungal preservative for liquid dosage forms; has low toxicity  SAR: increase activity as MW increases  Methylparaben (methyl-p-hydroxybenzoate): white crystalline powders; MOLDS  PropYlparaben (propyl-p-hydroxybenzoate): white crystalline powders; YEAST  Butylparaben (n-buty-p-hydroxybenzoate)  Ethylparaben (ethyl-p-hydroxybenzoate)
  • Chlorobutanol (1,1,1-trichloro-2- methyl-2-propanol, Chloretone®) at 0.1- 0.5% is bacteriostatic agent in pharmaceuticals for injections, ophthalmic use and intranasal administration
  • Benzylalcohol (Phenylcarbinol, Phenylmethanol): is a clear liquid with an aromatic odor; Uses: commonly used for vials for injectable drugs in 1-4% water or saline solution, local anesthetic effect, antiseptic in the treatment of pruritic skin condition.
  • Phenylethyl alcohol (Orange oil, Rose oil). Benzoic acid and its esters are naturally occurring in gum benzoin and in Peru and Tolu balsams Uses: Antiseptic in lotions, ointments and MW; Preservative in foods and pharmaceuticals at low pH Sodium benzoate Sodium propionate
  • Sorbic acid (2,4-hexadienoic acid): effective antifungal preservatives esp. in preparations containing sugar Potassium sorbate Phenylmercuric nitrate: preservative in injectable drugs, bacteriostatic efficacy is reduced in the presence of serum Phenylmercuric acetate (acetoxyphenylmercury) occurs as white prisms.
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  • Answer on Pre-Test •Which of the following agents is not used for local candidiasis? A. Nystatin B. Gentian Violet C. Griseofulvin D.Miconazole E. Clotrimazole
  • Fungal infections are caused by microscopic organisms that can invade epithelial tissue caused by yeast, molds etc. Fungal infections classification: o Superficial infections (Cutaneous): caused by dermatophytes → incidence rate is high. o Deep-seated mycoses: transmitted from one host to another.
  • Systemic infections are caused by the inhalation of spores affecting deeper tissues and organs and cause fungal pneumonia. This pneumonia cannot be transmitted from human to human.
  • Opportunistic Fungal infection: can cause life threatening infection to immunocompromised patients like patient with leukemia, cancer, HIV, diabetes and patients currently using immunosuppressive agents, cytotoxins, irradiation and even steroids.
  • Subcutaneous mycoses: refers to a group of fungal disease which both the skin and subcutaneous tissues are involved (internal organs are not affected) Characteristics: soil saprophytes of very low grade virulence and invasive ability and they gain access as a result of trauma to the tissue.
  • Skin: formidable barrier to drug penetration Fatty acid and Derivatives: all fatty acid and fatty acid derivatives (salts) have antifungal properties due to sebum fraction (part of innate immune system) SAR: higher molecular weight fatty acid have the advantage of having lower volatility; salt form are fungicidal
  • Propionic acid: non-irritating and non-toxic; present in perspiration or sweat; around 0.01% is fungicidal. Zinc propionate: used as fungicide on adhesive tapes Sodium caprylate and Zinc caprylate
  • Undecylenic acid (10-undecenoic acid, Desenex, Cruex): obtained from the destructive distillation of castor oil (ricinoleic acid) Use: treatment of athlete’s foot Triacetin (Glyceryl triacetate, Enzactin®, Fungacetin®): is a fungicide, a colorless oily liquid that release acetic acid upon hydrolysis.
  • Salicylic acid (use: antifungal and keratolytic) and Resorcinol (m- hydroxyphenol) (use: antiseptic and keratolytic) Benzoic acid: only antifungal that cannot penetrate the skin. Should be use in combination to provide therapeutic effect.
  • Phenol and their derivatives:  MOA: interfere with cell membrane integrity and function in susceptible fungi. Haloprogin (Halotex®): white to pale yellow and photosenstive 1% cream for the treatment of superficial tinea infection. Clioquinol (Vioform®): spongy, light- sensitive, yellowish white powder; substitute for iodoform  Use: tx of jock itch and athlete’s foot, 3% tx of vaginitis
  • Ciclopirox olamine (Loprox®): a broad spectrum antifungal agent used topically.  AOC: cutaneous candidiasis, Tinea corporis, Tinea cruris, Tinea pedis, and Tinea versicolor.  Second line agent for onychomycosis  MOA:  Low concentration: block the transport of amino acids into the cell  High concentration: lost of membrane integrity and cellular constituents
  • Flucytosine (5-FC, Ancobon®): orally active, narrow spectrum antifungal agent.  MOA: incorporation of fluorinated pyrimidine to fungal RNA following selective deamination of 5- fluouracil, which is an anti-metabolite that inhibits thymidylate synthethase and thus DNA synthesis refer to figure 6.3  Use: tx of systemic Candida and Cryptococcus spp. infections.
  • Polyenes: isolated from soil bacterium Streptomyces and has the structural requirement: o Large lactone ring (26 C: Natamycin; 38 C: Amphotericin B and Nystatin) o Series of OH groups on the acid portion of the ring o Glycosidically linked deoxyaminohexose sugar __________ o Conjugated double bonds (Natamycin is pentaene; Nystatin is hexaene; amphotericin B is heptaene)
  • Polyenes cont... o Broad spectrum anti-fungal agents against pathogenic yeast, molds and dermatophytes (with anti-protozoal properties) o Use of polyenes is limited because: 1) toxicity of drugs 2) low water solubility 3) poor chemical stability o Topical agents for superficial fungal infections
  •  Binds with sterols in cell membrane as “false membrane” component (-static at LOW concentration); generalized membrane (- cidal at HIGH concentration) and interferes permeability and transport functions.  Can form a pore in the membrane, creating a transmembrane ion-channel resulting in the loss of intracellular potassium ions.
  • Amphotericin B (Fungizone®): isolated in 1956 by Gold et. al from ______________  Amphoteric substance  Used to treat serious, potentially life threatening infections  Parenteral form (except IM) is an aqueous colloidal dispersion stabilized by sodium deoxycholate (Note: NSS is not use, WHY???)
  •  Selective action on the CM of fungi and some protozoa due to the affinity for _______ than cholesterol  Limitation (Ampothericin B) for use due to: o Nephrotoxicity (80%) o Generalized toxic reactions (fever, headache, anorexia, GI distress, malaise) o Hypokalemia, anemia o Pain at the injection site and thrombophlebitis o Hemolysis o Intrathecal route: neurotoxicity
  • Nystatin (Mycostatin®) isolated by Hazen and Brown (1951) from ________ The ring (aglycone) is called as ______ Natamycin (Natacyn®) obtained from _______ Treatment of conjuctivitis, blepharitis and keratitis
  • Griseofulvin (Grisovin®) 1st reported by Oxford et. al and was isolated from ____________  Note to pharmacist in dispensing Griseofulvin (-static)  Adverse effects: rash/urticaria, GI upset, headache, dizzines and insomia  MOA: Mitotic spindle poison (binds with the tubulin dimes required for microtubule assembly)
  •  Result of random screening  MOA: interfere early step of ergosterol biosynthesis: inhibition of squalene epoxidase (increase squalene concentration destabilizes the fungal cell membrane) epoxidation  ring opening (squalene zipper)  ergosterol biosynthesis  Activity (1) –static against pathogenic yeast and –cidal against dermatophytes and filamentous fungi
  • Naftifine HCl (Naftin): 1% cream/gel is used topically against ringworm, athlete’s foot and jock itch Terbinafine HCl (Lamisil) use is same with Naftifine but active against onychomycosis Terbenafine > Naftifine Tolnaftate (Tinactin): thioester of β- naphthol that inhibits squalene epoxidasase (-cidal)
  •  Clotrimazole  Econazole nitrate  Butoconazole nitrate  Sulconazole nitrate  Oxiconazole  Tioconazole  Represents a class of synthetic antifungal agents with a broad spectrum of activity and possess a unique mechanism of action.  Miconazole nitrate  Ketoconzazole  Terconazole  Itraconazole  Fluconazole  Voriconazole: newest among azole  Posaconazole: Phase II
  • N X N (CH2)n C R1 R2 Ar The triazole or imidazole ring are essential for the activity, the N 3 binds to the ferric iron atom in the heme prosthetic group to provent the activation of oxygen for insertion into lanosterol. The activity: X=N > X=CH atom of azole ring 1 The substitution must on the N ,other position will lose the activity The 2,4 position of aromatic ring are intruduced eletron withdrawing group,such as, F,Cl, will increase antifungal activity. the varying of R1 and R2 can be : R1= OH, or R, R2 formed a 1,3 dioxapetane.
  • Inhibition of cytochrome P-450 enzyme that catalyzes 14-- demethylation of lanosterol to ergosterol, accumulation of 14- methylated sterols cause permeability disturbance.
  • Clotrimazole (Canesten): broad- spectrum, used topically for the treatment of tinea and candidiasis and vulvovaginal candidiasis (tablet) SE: severe GI disturbances MOA: interferes with amino acid transport into the organism by an action of CM Econazole Nitrate (Spectazole) Butoconazole Nitrate (Femstat)
  • Sulconazole Nitrate (Exelderm) Oxiconazole Nitrate (Oxistat) Tioconazole (Vagistat): useful for vulvovaginal candidiasis. More effective against Torulopsis glabrata. Terconazole (Terazole): exclusively for the control of vulvovaginal monolialiasis
  •  Miconazole Nitrate (Daktarin): treatment for systemic fungal infection and chronic mucocutaneous candidiasis. AE: Thrombophlebitis, pruritus, fever, GI upset  Ketoconazole (Nizoral): 1st orally active broad spectrum (imidazole); useful for systemic infection, HEPATOTOXIC RPh’s Note: dispensing and DI
  • Itraconazole (Sporanox): one Orally active, broad spectrum Acidic environment requires for optimum absorption Food enhances absorption 99% protein bound, increase plasma concentration of anti-histamines Important alternative to Ketoconazole
  •  Fluconazole (Diflucan): the only water soluble azole (bis-triazole) with broad spectrum of activity.  Excellent oral bioavailability  Plasma protein binding is <10%  Recommended for the treatment and prophylaxis of disseminated and deep organ candidiasis Agent of choice: cryptococcal meningitis  DOC: fungal meningitis
  • Terconazole (Terazol) AE: Thrombophlebitis, pruritus, fever, GI upset  Voriconazole  Posoconazole
  •  Inhibitor of D14 reductase and D7 – D8 isomerase  Amorolfine
  • Echinocanadins: large cyclic peptides linked to a long fatty acid. Products: Caspofungin, Micafungin, Anidulafungin. MOA: inhibits the synthesis of 1,3-β-d- glucan synthase resulting to the disruption of the fungal cell wall and cell death. Non competitive inhibitor of 1,3-β-d-glucan synthase
  • A cyclic depsipeptide produced by ______________ MOA: act as a tight binding noncompetitive inhibitor of the enzyme inositol phosphorylceramide synthase. IPC synthase: essential for fungal sphingolipid biosynthesis
  •  
  •  Obtained by ____________ on the basis of model compounds that is used as antibacterial agent for local, systemic and/or urinary tract infections.  Examples: quinolones, heterocyclic (nitro) compounds and sulfonamides.
  • Patterned after _________ which is a ___________. Isosteric heterocylic groupings like: o Napthyridines: Nalidixic acid, Enoxacin o Cinnolines: Cinoxacin o Quinolones/Fluoroquinolones: Norfloxacin, Ciprofloxacin, Ofloxacin, Lomefloxacin, Sparfloxacin
  • First generation quinolones o Highly protein bound o Mostly used for UTIs Fluoroquinolones (2nd to 4th generation) o Modified 1st generation quinolones o Not highly protein bound o Wide distribution to urine and other tissue; limited CSF penetration o 2nd generation Norfloxacin and Enoxacin also indicated for STD like uncomplicated gonorrhea and chanroid (enoxacin)
  • Board Questions •Mechanism of action of quinolones: A. Injury to plasma membrane B. Inhibition of DNA gyrase C. Protein synthesis inhibition D.Production of toxic free radicals
  • Largely confined to G- Urinary pathogens, Escherichia, Klebsiella, Enterobacter, Citrobacter, Proteus Fluoroquinolones: effective against P. aeruginosa, N. gonorrhea, H. influenzae, G+ cocci, anaerobes Useful for penicillin resistant gonococci, methicillin resistant Staph. aureus and aminoglycoside resistant P. aeuruginosa.
  •  Drug interaction: o Decrease absorption of Al, Mg and Ca antacids o CYP450 inhibition  Adverse effects: o CNS: headache, irritability, tremors, sleep disorders, vertigo, anxiety, agitation, deleurium, hallucinations, seizure (rare) o GI: N & V o Allergic skin reaction: rashes, urticaria, pruritus o CV: torsades de pointes (rare) o Muskoskeletal: rupture tendon o Neurologic: polyneuropathy
  • Drug Names Spectrum 1st Nalidixic acid (NeGram) Cinoxacin Gram– but bot Pseudomonas species 2nd Norfloxacin Ciprofloxacin Enoxacin Ofloxacin Gram– (including Pseudomonas spp., some Gram+ (S. aureus) and some atypical microorganisms 3rd Levofloxacin Sparfloxacin Moxifloxacin Gemifloxacin Same as 2nd generation with extended G+ and atypical coverage 4th Trovafloxacin Same as 3rd generation with broad anaerobic coverage
  • Widely distributed in the body (CSF) Food delays absorption Binds divalent cation (decrease absorption) Increase effect of warfarin AOC for gastroenteritis caused by G- bacilli Used for acute and chronic UTI, VD and chronic infections involving renal tissues
  • Resembles ciprofloxacin in antibacterial spectrum and potency; increased concentration in CSF Superior oral absorption and bioavailability Food delays absorption Uses: LRTI: bronchitis and pneumonia, PID, acute gonococcal urethritis with Doxycycline, UTI, Prostatitis, Infection of the skin and soft tissues
  • •More potent optical isomer of ofloxacin: A. Opto B. Cis C. Levo D.Trans E. Dextro Board Questions
  • Spectrum: G-, G+ (S. aureus including MRSA and S. pneumoniae) Legionella pneumophila, atypical respiratory pathogens, M. tuberculosis Indications: Chronic bronchitis and CAP, Nosocomial pneumonia, SSTIs, intra-abdominal infections ADR: Blood glucose disturbances in DM patients, QTC prolongation, torsades de pointes, arrhythmias, N & V and GI Upset
  •  Safety and efficacy not established in patients < 18 y/o  Spectrum: G- (S. aureus including MRSA and S. pneumoniae), atypical respiratory pathogens (Legionella pneumophila, C. pneumoniae and M. pneumoniae) M. tuberculosis, G- anaerobes  Indications: Chronic bronchitis and CAP, Bacterial conjunctivitis, sinusitis  ADR: blood glucose disturbances in DM patients, QTC prolongation, torsades de pointes, arryhtmias, N & V and GI upset
  • Only quinolone that is taken OD Most phototoxic: WHY??? Primarily used for acute bacterial exacerbations of chronic bronchitis and prophylaxis of infections following transurethral surgery For acute cystitis and chronic UTI
  •  Higher potency against G+ bacteria  Skin and soft tissue infection in LRTI and PID  Bacterial gastroenteritis and cholecystitis
  • UTI Gonorrhea: β-lactam resistant strains Diarrhea: caused by Shigella, toxigenic E. coli, Salmonella, thypoid Respiratory infection: Bacterial (Haemophilus, Strep spp., Pseudomonas) and non bacterial like Chlamydia, Mycoplasma and Legionella Osteomyelitis
  • First nitroheterocyclic compound to be introduced into chemotherapy. Derivatives of 5-nitro-2-furaldehyde, formed on reaction with the appropriate hydrazine or amine derivative. Antiprotozoal (Nifurtimox) in the tx of trypanosomiasis and leishmaniasis Ameobacide (Metronidazole) AE: mutagenic and carcinogenic
  • SAR: Anti-microbial property is present only when the nitro group is in the 5- position. MOA: reduction (nitrofuran reductase) of the nitro group coupled with the formation of free radicals (reactive intermediates) which cause damage to ribosomal proteins especially DNA, causing inhibition of DNA, RNA, protein, and cell wall synthesis.
  • Nitrofurazone: topically in the treatment of burns and prevent bacterial infection associated with skin grafts Furazolidone: recommended for the oral treatment of bacterial or protozoal diarrhea Nitrofurantoin: suitable for oral use in the treatment of UTI. Microcrystalline form improve GI tolerance without interfering oral absorption
  • Board Questions •Methenamine is decomposed into ____ at a urine pH of 5.5. This is responsible for methenamine’s urinary tract antiseptic property: A. Formaldehyde B. Acetone C. Carboxylic acid D. Ethanol
  • Methenamine: prepared by evaporating a solution of formaldehyde and strong ammonia water to dryness. MOA: antibacterial activity depends on liberation of formaldehyde and enhanced by acidifying with sodium biphosphate or ammonium chloride Tx for chronic UTI
  • Ineffective for urease containing microorganism – WHY??? Salt form like Methenamine mandelate (Mandelamine) and Methenamine hippurate (Hiprex) are used as urinary antiseptic.
  • Alleviate pain and discomfort caused by UTI Soluble and concentrates in urine Phenazopyridine HCl (Pyridium) Formerly used as urinary antiseptic Local analgesic effect on the mucosa of the UT; Used in combination (Azo-gantrisin and Urobiotic) May tint the urine _______________ The stain is removed by sodium dithionite
  • Causative organism — Mycobacterium tuberculosis; live inside the macrophages and lysosomes; it is a gram positive acid fast bacillus. Usual locations of Tuberculosis — Lungs (PTB), Bones, Intestine, Kidney, Intestine, Lymph Nodes, Breast and Tubercular Meningitis.  Management: “shotgun therapy”
  • Aim of therapy — treatment must be for longer period because response to chemotherapy is slow, because of: o Slow rate of growth o Intracellular location o Large number of actively multiplying bacteria must be killed. (best drug is Isoniazid)
  • • Combination therapy in the treatment of tuberculosis contain the following drugs, except: A. Ethambutol B. Rifampicin C. Isoniazid D. Streptomycin E. A, B and C Board Questions
  • Why combination therapy is given in TB? o To broaden the spectrum o To reduce the toxicity of individual drugs o To prevent the emergence of resistance 2 types o 1st line drugs (RIPES) o 2nd line drugs (Aminoglycosides, p- aminosalicylic acid (PAS), capreomycin, ciprofloxacin, clofazimine, cycloserine, ethionamide, levofoxacin, rifabutin)
  • Current recommended treatment for pulmonary TB has three regimens: 6 Month Regimen—virtually 100% effective, more expensive. (usually only used in pulmonary TB) First 2 months— RIPE; Next 4 months— RIP
  •  Prophylactic Dose: Isoniazid: dose is 300mg/day (5mg/kg/day) or 900mg twice weekly for 6 to 12 months in case of immunocompromised patients. Rifampicin: prophylaxis for the patients who are unable to take isoniazid; have close contact with a case of active TB caused by an isoniazid resistant Rifampicin-susceptible strain.
  • Isoniazid: safest, most potent and effective against all forms of M. tuberculosis; Bactericidal. Readily absorbed from the GIT Toxic effects: I-N-H Metabolism and excretion: __________ Slow acetylators: Egyptians Rapid acetylators: Eskimos, Asian Filipinos are slow acetylators, Lin et. al., 1994
  • Ethionamide: secondary drug for the treatment of TB Used in the txt of INH resistant TB AE: GI intolerance, visual disturbances, hepatotoxicity.
  • Pyrazinamide: first line agent in short term TB Effective in low pH environment Penetrates inflamed meninges Synthetic analogue of Nicotinamide Can kill TB bacilli in acidic pH up to 5.5 (intracellular, within the macrophage and lysosome) Cannot kill TB bacilli in the blood because of high pH
  • Mechanism of Action: Drug is converted into Pyrazinoic acid by Pyrazinamidase in M. tuberculosis and kills the bacteria, the target and the mechanism of action is unknown. SE: interfere uric acid secretion
  • Ethambutol: active against dividing mycobacteria  Stereospecific; in combination with other antitubercular drug specially in PTB  Mechanism of Action:  Inhibits the synthesis of Arabino-galactan which is an essential component of the mycobacterial cell wall.  Inhibition of the incorporation of mycolic acid into the cell wall of the microorganisms
  • Adverse effects: Retinobulbar optic neuritis (most common)—loss of visual acuity, red- green color blindness and blindness. Should not be given to children Hyperuricemia—may occur Hypersensitivity—very rare
  • Aminosalicylic acid and aminosalicylate sodium second agent for TB  MOA: prevents incorporation of PABA in dehydrofolic acid molecule Clofazimine: basic red dye that exerts a slow bactericidal effects on M. leprae  Anti-inflammatory and immune-modulating effects  Tx of skin lesions caused by M. ulcerans  AE: sever GI intolerance, skin pigmentation, ichtyosis, dryness, rash, pruritus.
  • Rifampin (Rifampicin) It is a complex semisynthetic derivative of Rifamycin produced by _____________ Most active first line agent against TB When taken with paracetamol, APAP is inactivated Can tint the urine, stool, saliva, tears, skin _____________ AE: ______(common) and allergic reactions
  • MOA: Rifampicin inhibits DNA dependent RNA polymerase which is responsible for RNA synthesis
  • Drugs that can affect urine color • Red or pink urine: Rifampicin (common), phenazopyridine • Orange urine: Rifampicin, sulfasalazine • Blue or green urine: Amitriptyline, indomethacin, propofol • Dark brown/tea-colored urine: Chloroquine, primaquine, metronidazole, nitrofurantoin
  • Rifabutin: prophylaxis of disseminated MAC in AIDS patients Cycloserine: isolated from Strep. orchidaceus, Strep. garyphalus, Strep. lavendulus MOA: prevents the synthesis of cross linking peptide in the formation of bacterial cell walls Recommended for patients who failed to respond to other anti-TB drugs or resistant TB
  • Sterile capreomycin sulfate: aminoglycoside, strongly basic cyclic peptide isolated from Strep. capreolus Second line agent, alternative to streptomycin
  • Isoniazid Peripheral Neuropathy Rifampicin Cholestatic jaundice + renal toxicity + Flu like syndrome Pyrazinamide Hepatotoxicity + Hypeuricemia Ethambutol Retinobulbar optic neuritis
  • Metronidazole Spectrum of activity: anaerobic, microaerophillic bacteria and protozoa “triad of features” which includes antiamebic, antigiardiasis, and anti- trichomonal.
  • Mechanism of action: enters bacteria via cell diffusion Activated via single reduction step by bacteria  forms radicals  reacts with nucleic acid(by covalently binding the 5- nitro group to DNA)  cell death
  • Diloxanide: esters are to be activated to exert amebicidal activity. Tx of asymptomatic carriers of E. histolytica 8-hydroxyquinoline: antibacterial and antifungal, parent compound Iodoquinol: tx of acute and chronic intestinal amoebiasis AE: neuropathy
  • Emetine and dehydroemetine: alkaloids obtained from Ipecac o Amoebicidal o Protoplasmic poison o Tx fo liver disease since alkaloids concentrates mainly at the liver o Tx of balantidial dysentery and fluke infestations
  • Pentamidine isethionate: oTx of pneumonia cause by P. carinii oTx for the prophylaxis of African trypanosomiasis oTx for visceral leishmaniaisis
  • Atovaquone: highly resistant to malaria, highly lipophillic, water insoluble analogue of ubiquinone 6 o Alternative tx of PCP caused by P. carinii o Originally an antimalarial Plasmodium falciparum develops tolerance to its action o High fat diet to improve absorption
  • Eflornithine: inhibitor of ornithine decarboxylase o Tx of West African sleeping sickness caused by T. gambiense Nifurtimox: nitrofuran derivative o Tx for acute and DOC for chronic Chaga’s disease
  • Benznidazole: nitroimidazole derivative as an alternative in the treatment of Chaga’s disease o SE: peripheral neuropathy, bone marrow supression Melarsoprol: DOC for later stages of African trypanosomiasis o Excellent penetration into the CNS o Causes arsenic toxicity
  • Sodium stibogluconate: pentavalent antimony-compound intended primarily for the tx of various leishmaniasis (DOC) Dimercaprol: heavy metal poison MOA: chelation Suramin sodium: DOC for long term prophylatic agent for African trypanosomiasis
  • Drugs that have the capability of ridding the body of parasitic worms or helminths oPlatyhelminthes: tapeworms and flukes oNemathelminthes: nematodes or true round worms
  • Ascaris lumbricoides (round worm) - “PAM” Pyrantel palmoate, Albendazole, Mebendazole Hookworm -“PAM” Pyrantel palmoate, Albendazole, Mebendazole o Ancylostoma duodenale (old-world hookworm) o Necator americanus (new-world hookworm) Trichuris (Trichuris trichuria)- “AM” Albendazole, Mebendazole
  • Strongyloides - Ivermectin Enterobius vermivularis - “PM” Pyrantel palmoate, Mebendazole Trichinella - Mebendazole Cutaneous larva migrans - “AI” Albendazole, Ivermectin Onchocerca volvulus - Ivermectin
  • Schistosoma haematobium - Praziquantel Schistosoma mansoni - Praziquantel Schistosoma japonicum - Praziquantel Paragonimus westermani - Praziquantel Fasciola hepatica - Bithionol or Triclalbendazole Fasciolopsis buski - Praziquantel or Niclosamide
  • Taenia saginata - Praziquantel or Niclosamide Taenia solium - Praziquantel or Niclosamide Hymenolepsis nana - Niclosamide Cysticercosis - Albendazole Diphylobothrium latum - Praziquantel or Niclosamide Echinococcus granulosus: Albendazole
  • Piperazine: MOA: increase the resting potential of the helminth muscle so that the muscle membrane is supressed leading to flaccid paralysis Diethylcarbamazepine citrate: selective anthelmintic activity against filariasis and ascariasis
  • Pyrantel pamoate: a depolarizing neuromuscular blocking agent Antagonize piperazine ADR: GI effect MOA: promotes depolarization of the helminth’s myoneural junction and cholinesterase inhibition  spastic paralysis and loss of muscle activity
  • Thiabendazole Mebendazole: broad spectrum anthelmintic activity similar with thiabendazole MOA: inhibition of glucose uptake leading to depleted glycogen storage  decrease ATP synthesis AE: abdominal discomfort and teratogenic
  • Albendazole: broad spectrum anthelmintic activity against nematodes (intestinal) Single-dose tx for ascariasis, hookworm, and trichuriasis Multiple dose therapy with albendazole for the tx of pinworm, threadworm, capillariasis, chlornorchiasis and hydatid disease.
  • Answer on Pre-Test • All of the following are effective and clinically useful against worm infestation caused by Ascaris lumbricoides, except: A. Niridazole B. Mebendazole C. Piperazine D. Pyrantel pamoate E. Thiabendazole
  • Niridazole: Active against blood trematodes: Schistosoma hematobium, S. japonicum and S. mansoni. MOA: inhibits the conversion of the active form of schistosomal glycogen phosphorylase into inactive form
  • Niclosamide: taenicide, a saline purge 1- 2 hrs after ingestion of niclosamide is recommended to remove the scolex and worm segments Potent taenicide that segments worms and scolex MOA: inhibition of glucose uptake, inhibition of energy production by anaerobic metabolism and inhibition of inorganic phosphate incorporation into ATP
  • Bithionol: chlorinated bisphenol, fasciolicide and taenicide Oxamniquine: antischistosomial (S. mansoni) agent for intestinal schistosomiasis. Activated mainly by esterification and alkylates the DNA of helminth  inhibition of nucleic acid metabolism
  • Praziquantel: an isoquinoline derivative (levo form most active) broad spectrum against flukes DOC: blood flukes MOA: produces tetanic-like contraction within the muscle system of the fluke (alteration in the influx of calcium ions) leading to segment worms
  • Ivermectin: a 16 membered macrocyclic lactone obtained from Strep. avermitilis  MOA: act as GABA agonist or as an inducer of chloride ion inlfux leading to hyperpolarization and muscle paralysis.  Used in controlling endo and ecto parasites in domestic animals  Effective for onchocerciaris in humans that is caused by Oncocerca volvulus
  • Scabicide: compounds used to control mites (Sarcoptes scabiei) Pediculicide: used to eliminated head, body and crab lice, fleas
  • Benzoyl benzoate (benzyl alcohol + benzoyl chloride): ester from Peru balsam, topical scabicide Lindane: halogenated hydrocarbon with insecticidal activity o A direct poison, fumigant effect, acts as a stomach poison o Tx of scabies and pediculosis
  • Crotamiton: topical tx of scabies Permethrin: synthetic pyrehtrinoid compound o Exerts lethal action against lice, ticks, mites and fleas o Pediculicide for the treatment of headlice
  • •Which of the following can cause sunburn? A. Amoxicillin B. Sulfonamindes C. Macrolides D.Quinolones E. Tetracyclines Board Questions
  • Antibiotics: natural products biosynthesized by microorganisms that are toxic to other species of microorganisms. SYNTHETIC ANTIBACTERIAL AGENTS
  •  Sulfonamides were the first successful selectively toxic antibacterial drugs. _________ was discovered by ______ in 1936, and used to successfully treat puerperal sepsis (childbirth fever) in London. First effective chemotherapeutic agent to cure bacterial infections in humans.
  • • Sulfonamide toxicities includes the following: I. Crystalluria II. Rashes III. Nausea A. I only B. II and III C. I and III D.I and II E. I, II and III Board Questions
  • H2N S N H R O O 1935: era of sulfa drugs
  • • A bright red dye that was found to create remarkable cures of streptococcal infections: A. Prontosil B. Methyl red C. Methyl orange D. All E. None Board Questions
  • •Sulfanilamide is: A. a type of sulfonamide B. Same as sulfonamide C. Generic of sulfonamide D. Salt of sulfonamide Board Questions
  • Prontosil: brilliant azo red dye which was found to protect against and cure Streptococcal infections in mice; it is converted to its active metabolite “sulfanilamide”  Sulfanilamide is a generic term that denotes: o Aniline-substituted sulfonamides/sulfanilamides o Prodrugs that generate active sulfanilamides o Non-aniline sulfonamide like mafenide acetate
  • Renal toxicity: Older sulfonamides crystallized in urine. Blood dyscrasias: Hemolytic anemia Dermal toxicity: Rashes, pruritus, erythema, SJS Rare but serious side effects: hepatitis, drug-induced fever Less serious side effects: headache, GI discomfort (nausea, loss of appetite)
  •  Spectrum of activity: G+ and G- bacteria, Nocardia spp. Chlamydia trachomatis, Protozoa, and Enteric bacteria,  ADR: CRANK  Classified according to use: o Oral absorbable (single, mix) o Oral non-absorbable o Topical agents o Sulfanilamide for Intestinal infections, Ulcerative colitis or Redution of Bacterial Flora
  • Sulfamethizole Sulfisoxazole: Sulfisoxazole acetyl (prodrug) Sulfisoxazole diolamine: salt form by adding enough diethanolamine, systemic and local (eye) infection Sulfamethazine: more soluble in acidic urine Sulfacetamide: antibacterial
  • Sulfachloropyridiazine Sulfapyridine Sulfamethoxazole Sulfadiazine Sulfadiazine sodium: administered as a 5% solution in sterile water IV for patient requiring an immediate high blood level of sulfonamide
  • Trisulfapyrimidines: oral suspension and tablet form; contains equal amount of sulfadiazine, sulfamerazine, sulfamethazine Sulfadoxine & pyrimethamine: tx of Plasmodium falciparum (pt with chloroquine resistance). Used for malaria prophylaxis for travellers where chloroquine resistant malaria is endemic
  • Sulfacetamide sodium: very soluble in water; used as eye drops Sulfisoxazole diolamine: short to intermiate acting sulfonamide IM, IV TriSulfa: contains sulfabenzamide, sulfacetamide, sulfathiozole As a vaginal cream in the tx of Haemophilus vaginalis
  •  Topical sulfonamides for burn therapy:  Mafenide acetate: homologue of the sulfanilamide molecule that is not inhibited by PABA  Effective against Clostridum welchii and for the prophylaxis for wounds  Silver sufadiazine and zinc salt: tx of infection against Pseudomonas spp. a very potent antimicrobial in the treatment of burns, scald and wound infections. Patient acceptance is better than mafenide.
  • Sulfasalazine: prodrug (m- aminosalicylic acid and sulfapyridine. Effective in treating ulcerative colitis
  • Trimethoprim: orally active dyaminopyridine structure, closely related to several anti-malarials, a potent antibacterial, tx of uncomplicated UTI Sulfamethoxazole and Trimethoprim: tx of chronic UTI. DOC for both complicated and uncomplicated UTI especially caused by enterobacteria. Rationale of the combination?
  • Reported to be effective against malaria and rickettsial infections. MOA: same with sulfonamides Cross resistance to sulfonamides Mainly use for treating _____________ caused by ______________ Aside from rodents (mice) ________ is another biological test animal to culture M. leprae.
  • •Drug of choice for leprosy: A. Dapsone B. Clofazimine C. Streptomycin D.Prothionaide E. Ethionamide Board Questions
  • Dapsone, DDS (Avlosulfone®): parent sulfone and prototype Treatment of both lepromatous and tuberculoid leprosy DOC: dermatitis herpetiformis Sometimes used with pyrimethamine for the tx of malaria and with TMP for PCP SE: Hemolytic anemia(G6PD), methemoglobinemia, toxic hepatic effects
  •  Widespread disease caused by __________ parasite coined from “mala aria” = bad air  Other names: ague, intermittent fever, marsh fever, The Fever  Vector: Female Anopheles mosquitos  Parasitic protozoans: Plasmodium vivax and P. falciparum, P. ovale and P. malariae (milder, rarely fatal) and P. knowlesi (zoonotic)
  •  Three potential ways to control malaria:  Vector control  Drug therapy  Vaccination
  • NAME DESCRIPTION Plasmodium falciparum 50% (most common), severe form, can infect 65% of the patient’s erythrocytes Plasmodium vivax 40% very chronic, recurrence is possible and can cause reinfection of the liver cells Plasmodium malariae 10%, relapses are common Plasmodium ovale Least common
  • Figure 7.1 pg. 243
  • CINCHONA ALKALOIDS Quinine Sulfate: lethal for all Plasmodium schizonts and gametocytes from P. vivax and P. malariae  Indicated for malaria caused by chloroquine- resistant P. falciparum strains  Used for nocturnal leg cramps  Side Effects: abortifacient Quinidine: more potent anti-malarial  Stereoisomer of quinine but is primary indicated for cardiac arrhythmias
  • CINCHONISM Cinchonism: toxic syndrome characterized by tinitus, headache, nausea, disturbed vision.
  • A semi-synthetic anti- malarial agent: A. Quinine B. Artemisinin C. Emetine D. Cycloguanil E. Mefloquine BOARD QUESTIONS
  • 4-AMINOQUINOLINES Chloroquine (Aralen®)  HCl: parenteral; PO4: oral tablet  Main anti-malarial drug for prophylaxis and treatment of malaria  Used also for extra-intestinal amoebiasis  DOC for erythrocytic falciparum malaria, except resistant strain  ADRs: retinopathy, hemolysis, muscle weakness, exacerbation of psoriasis, porphyria, impaired liver function Hydroxychloroquine (Plaquenil®)  High protein bound (remains in the body for over a month)
  • 4-AMINOQUINOLINES Amodiaquine  Prophylaxis for malaria  Associated with higher incidence of hepatitis and agranulocytosis Mefloquine (Lariam®)  Schizonticide (newest member)  Exacerbate mental disorders  DOC for malarial supression
  • 8-AMINOQUINOLINES Primaquine  Narrowest spectrum of activity  Most effective against malarial parasite in the liver but not effective against parasites within erythrocytes.  MOA: disruption of parasites mitochondria  DOC: for acute attack of Plasmodium vivax
  • POLYCYCLIC ANTIMALARIAL DRUGS Doxycycline: a tetracycline that inhibits the pathogen’s protein synthesis  Prophylaxis for malaria  CI in children and in areas with greatest sunlight Halfantrine: can arrest tissue conduction in cardiac muscles Lumefantrine: proposed MOA: inhibition of β- hematinin by forming complex with hemin
  • POLYCYCLIC ANTIMALARIAL DRUGS Quinacrine: most toxic antimalarial drug  Acridine dye (can cause yellow color of skin, tissues, etc.)  Treatment for malaria and a sclerosing agent Artemisinin
  • FIXED COMBINATION Sulfadoxine + Pyrimethamine (Fansidar®)  Prophylaxis and treatment of chloroquine resistant malaria  MOA: inhibition of folic acid biosynthesis and dihydrofolate reductase
  • FIXED COMBINATION Atovaquone and Proguanil (Malarone®)  Effective against erythrocytic and exoerythrocytic plasmodium  Used for resistant malaria  MOA: inhibition of dihydrofolate reductase and damage to the parasite’s mitochondria Proguanil is a prodrug of _________ Artemether and Lumefantrin: interfere heme metabolism  interfere parasites in erythrocytic stage
  • NEW DRUG APPROACHES Inhibition of non-mevalonate pathway  Fosmidomycin: isolated from Streptomyces fermentation broth in 1980.  Inhibits the enzyme DOXP reductoisomerase Inhibition of Glutathione reductase
  • Which of the following best described antibiotics? I. It is a product of metabolism II. It is a synthetic product produced as a structural analogue of a naturally occurring antibiotic (a biosynthetic product) III.It antagonizes the growth or survival of one or more species of microorganism IV.If it is potent, it is effective at low concentration
  • Antibacterial Antibiotics • Villemin’s “antibiosis”: concept of survival of the fittest • Waksman: an antibiotic or antibiotic substances is a substance produced by microorganism which has the capacity of inhibiting the growth and even destroying other microorganisms
  • Attributes of a good antibiotics, except: I. Exhibit sufficient selective toxicity II. Chemically stable III.Slow rates of biotransformation and rapid rates of elimination IV.Has narrow spectrum of activity to avoid toxicity
  • Which is true about the MOA of antibiotics? I. Inhibition of bacterial cell wall is a good sign of selective toxicity II. Competitive antagonist of pathogen’s metabolite III.Inhibition of pathogen’s protein synthesis IV.Inhibition of the integrity and function of microbial cell membrane
  • EXAMPLES OF SELECTIVE ACTION
  • •Anti-infectives agent that target ribosomes are said to be : A. Bacteriostatic/Fungistatic B. Pancidal C. Bactericidal/Fungicidal Board Questions
  • Site of Action Antibiotic Type of Activity Cell Wall Bacitracin Bactericidal Cephalosphorins Bactericidal Penicillins Bactericidal Vancomycin Teicoplanin Bactericidal Cell Membrane Amphotericin B Fungicidal Nystatin Fungicidal Ribosomes 50s CMC Bacteriostatic Erythromycins Bacteriostatic Lincomycins Bacteriostatic
  • Site of Action Antibiotic Type of Activity 30s AmiNOglycosides Bacteriostatic TCN Bacteriostatic Nucleic acids Actinomycin Pancidal Griseofulvin Fungistatic Drug Process affected Type of Activity Mitomycin C DNA synthesis Pancidal Rifampin mRNA synthesis Bactericidal
  • Question •Which of the following is/are example/s of beta-lactam antibiotics? I. Penicillins II.Beta lactamase inhibitors III.Cephalosporins IV.Monobactams
  • • Which of the following is not an example/s of beta-lactam antibiotics? A. Penicillins B. Beta lactamase inhibitors C. Cephalosporins D. Monobactams E. Quinolones Board Questions
  • Development of Penicillin • Earliest known antibiotic (historical prototype) • Sources (2) • Has beta-lactam thiazolidine ring • Derivative of 6-aminopenicillanic acid (6-APA)
  • • Benzylenicillin and early cephalosporins mainly active against gram positive bacteria. • “Broad spectrum” penicillin appeared: ampicillin, ureidopenicillins and cephalosporins: cefuroxime, cefotaxime • Carbapenems and latest generation of cephalosporins, e.g ceftazidime more active against gram negatives. Development of Penicillin
  • Mnemonics • FOR GRAM POSITIVE BACTERIA: • Corny Actors KNock Back Listerine in the Closet • Corynebacteria, Actinomyces, Nocardia, Bacillus, Listeria, and Clostridium. (plus Staph, and Strep - the t looks like a + sign)
  • Benzylpenicillin: Main Indications • Strep. pyogenes sepsis (from sore throat to fasciitis) • Pneumococcal pneumonia, meningitis • Meningococcal meningitis, sepsis • Infective endocarditis (Strep spp.) • Strep. group B sepsis • Diphtheria • Syphilis, leptospirosis
  • Organisms producing TEM1beta lactamase • Haemophilus influenzae • Neisseria gonorrhoeae • Bacteroides fragilis • Staphylococcus aureus • Escherichia coli
  • Penicillins and related products are generally safe but… • Allergic reactions: Rashes • Hypersensitivity: Urticaria immediately after penicillin after a further dose of any penicillin or cephalosporin • Most severe reaction: Anaphylaxis • Anaphylaxis: allergy of respiratory system characterized by diffuclty in breathing • Antidote: EPI
  • • Patient taking amoxicillin experience rashes after taking it orally, what might be the best alternative to penicillin? A. Aureomycin B. Erythromycin C. Lincomycin D. Spectinomycin E. All of these Board Questions
  • What antibiotics can be used in penicillin allergy (substitute)? • Macrolides: erythromycin, clarithromycin (mainly gram positive) • Quinolones: ciprofloxacin, levofloxacin (mainly gram positive) • Glycopeptides (serious infections) • Fusidic acid, rifampicin, clindamycin (mainly gram positive)
  • Remember what are the other beta lactams: • All penicillins: ampicillin, augmentin, piperacillin, cloxacillin • Cephalosporins: cefuroxime, cefotaxime, ceftriaxone, ceftazidime (5-10% cross sensitivity) • Monobactam: aztreonam (low cross sensitivity) • Carbapenems: imipenem, meropenem
  • •Which of the following is a depot penicillin preparation? A. Penicillin G Benzathine B. Benzylpenicillin C. Methicillin D.Phenoxymethylpenicillin E. Cloxacillin Board Questions
  • Natural/Biosynthetic Penicillins • Penicillin G • Penicillin G Procaine: a repository form (depot) • Penicillin G Benzathine: a depot form • Phenoxymethylpenicillin: first synthetic penicillin Pen G Sodium 1mg = 1667 units Pen G Procaine 1mg = 1009 units Pen G K+ 1mg = 1530 units
  • Penicillinase-sensitive • PenG • PenV • Ampicillin • Amoxicillin • Carbenicillin • Mezlocillin • Ticarcillin • Piperacillin
  • Penicillinase – resistant • Narrow spectrum of activity • Active against G+ cocci • Methicilllin: 2nd synthetic can cause interstitial nephritis • Nafcillin • Oxacillin • Cloxacillin • Dicloxacillin Isoxazoyl penicillin
  • Broader spectrum penicillins (α-amino group) • Ampicillin: agent of choice for Haemophilus influenza infections with probenecid used for gonorrhea • Bacampicillin HCl: prodrug • Amoxicillin: a p-hydroxy analog of ampicillin cover most organisms hit by penicillin but also E. coli, some Proteus (cause UTI’s)
  • Broader spectrum penicillins (α-amino group) • Augmentin stable to TEM1 β- lactamase because of the clavulanic acid therefore more active than ampicillin • Tazocin: broader coverage than Augmentin against gram negatives including Pseudomonas
  • Extended Spectrum Penicillins • Carboxypenicillins ▫ Carbenicillin (disodium and indanyl sodium salts): UTI ▫ Ticarcillin: isostere of carbenicillin ▫ Has greater potency against P. aeruginosa and Bacteroides • Acylureidopenicillins ▫ Mezlocillin ▫ Piperacillin
  • • Penicillin is the drug of choice for the following anti-infective conditions, except: A. Gonococcal infection B. Pneumococcal infection C. Treponema infection D. Streptococcal infection E. Pseudomonal infection Board Questions
  • Acid Sensitive • PenG • Methicillin • Carbenicillin • Mezlocillin • Ticarcillin • Piperacillin Acid Resistant • Penicillin V • Ampicillin • Amoxicillin • Nafcillin • Oxacillin • Cloxacilin • Dicloxacillin
  • β-lactamase inhibitors
  • B-lactamase inhibitors • Class I inhibitors “suicide substrates” ▫ Clavulanic acid (has a strained beta- lactam ring and has no amino acyl side chain compared to other B-lactam antibiotics) from Strep. clavugeris ▫ Sulbactam ▫ Tazobactam: a penicillanic acid sulfone
  • •Class II inhibitors: “carbapenems” ▫ Thienamycin from ___________ ▫ Imipinem – cilastatin (inhibitor of ________) ▫ Ertapenem: is a synthetic 1-beta- methylcarbapenem. ▫ Meropenem ▫ Biapenem β-lactamase inhibitors 2nd generation carbapenems
  • Carbapenems: sensitive to dehydropeptidase I • Absence of sulfur atom in the bicylic ring system • It has no aminoacyl side chain • Active against many highly penicillin resistant-strains of pneumonococci. • Beta-lactam of choice for the treatment of enterobacter infections. • SE: N & V, diarrhea, skin rash, renal failure (Imipinem), seizures
  • Carbapenems: sensitive to dehydropeptidase I • Imipenem + Meropenem and Biapenem: have a very broad spectrum activity against gram-negative bacteria, anaerobes, Streps. • Now used to treat gram negative infections due to so called ESBL producing organisms e.g. E. coli, Klebsiella • Ertapenem is a new member of the group but its not active against Pseudomonas
  • Drug Combination •Co-amoxiclav •Primaxin® •Tazocin® •Unasyn ® •Co-trimoxazole
  • Background: Cephalosporins • Discovered by Guiseppe Brotzü in 1945 from ___________________ • Abraham and Newton discovered three principal antibiotic components as: • Cephalosporin P1 (steroidal type) • Cephalosporin N/Penicillin N (Gram negative> Gram positive) • Cephalosporin C (dihydrothiazine ring)
  • Adverse Reactions • Hypersensitivity: rashes, anaphylaxis, cross-sensitivity • Diarrhea: disruption of normal flora • Nephritis: Methicillin • Hemorrhage: anti-pseudomonal • Electrolyte disturbance
  • Drug Interactions • with Probenecid: inhibit renal excretion of penicillin (potentiation) • with Aminoglycosides: penicillin increase entry (synergism): may form inactive complex if mixed in infusion fluid • With –static drugs antagonism
  • • Contains beta-lactam dihydrothiazine ring • Derivative of 7-aminocephalosporanic acid Background: Cephalosporins
  • • Cefuroxime: surgical prophylaxis • Cefotaxime/ceftriaxone: meningitis nosocomial infections excluding Pseudomonal infection • Ceftazidime: nosocomial infections including Pseudomonal Cephalosporins: main uses
  • Classification Activity G+ (H) Activity G- (L) 1st generation Highest Lowest 2nd generation Low Lower 3rd generation Lower Higher 4th generation Lowest Highest
  • Oral Cephalosporins • Cephalexin • Cephradine (Parenteral) • Cefadroxil • Cefaclor • Loracarbef (1st, carbacephems) • Cefprozil • Cefuroxime (Parenteral) • Cefpodoxime • Cefixime • Ceftibuten
  • Parenteral Cephalosporins • Cephradine (Oral) • Cephalothin • Cephapirin • Cefazolin • Cefamandole • Cefonicid • Ceforanide • Cefoxitin • Cefotetan • Cefmetazole • Cefuroxime (Oral) • Cefoperazone • Cefotaxime • Ceftizoxime • Ceftriaxone • Ceftazidime • Cefepime • Cefpirome
  • • Which of the following is an example of 2nd generation cephalosporins? I. Cefalexin II. Cefuroxime III. Cefaclor A. I and II only B. I and III C. II and III only D. II only E. III only Board Questions
  • Cephalosporin Mnemonics 1st Gen 2nd Gen 3rd Gen 4th Gen 5th Gen “Ceph” Except: Cefadroxil Cefazolin “Cef” DO NOT END in –one and – ime except: Loracarbef Cefpodoxime End with – one and –ime except: Ceftibuten Moxalactam Cephalexin Cephalotin Cephapirin Cephradine *Cefuroxime Cefaclor Cefamandole Cefonicid Cefotetan Cefoxitin Cefmetazole Cefprozil *Cefuroxime Ceftazidime Ceftizoxime Ceftriaxone Cefixime Cefoperazone Cefotaxime Cepefime Cefpirome Cefoselis Cefcidin Ceftobiprole Ceftaroline
  • First Generation Cephalosporins • Very active against Gram-positive cocci. • Inactive against MRSA strain of Staph., E.coli, K. pneumoniae, P. mirabilis • DO NOT CROSS BBB • Broad spectrum, nontoxic • First generation: PEcK
  • Second Generation Cephalosporins • Active against organisms inhibited by first-generation, has extended Gram- negative coverage • Cannot pass BBB • Not active against enterococci or P. aeruginosa • Second generation: HENPEcK
  • Third Generation Cephalosporins • Has extended Gram-negative coverage; some products can pass BBB • Active against Citrobacter, Providencia • Effective against beta-lactamase producing strain of Hemophilus and Neisseria • Third generation: HENPEcKSSS
  • Fourth Generation Cephalosporins • More resistant to hydrolysis by chromosomal beta-lactamase • Has good activity against P. aeruginosa, Enterobacter, S. aureus, and S. pneumoniae • Fourth generation: P. aeruginosa
  • Fifth Generation Cephalosporins •Enterococcus faecium •Staphylococcus aureus •Klebsiella pneumoniae •Acinetobacter baumanii •Pseudomonas aeruginosa •Enterobacter spp
  • Monobactams • Relatively resistant to beta-lactamases and active against Gram-negative rods • No activity on Gram-positive and anaerobes
  • Monobactams • Aztreonam: poor oral bioavailability, relatively non- toxic • Tigemonam: orally active monobactam
  • • Which of the following statements is not true regarding the aminoglycosides antibiotics? A. they are highly ionized in solution B. they are antibactericidal C. they are more effective in alkaline medium D. they are ototoxic and nephrotoxic E. they are easily absorbed after oral administration Board Questions
  • AmiNOglycosides • Contain an amino sugar that are linked by ______ • Contain a highly substituted 1,3- diaminocyclohexane central ring ▫ Deoxystreptamine (KNGT) ▫ Streptadine • Potent, broad-spectrum activity • Strongly basic (sulfates)
  • AmiNOglycosides
  • • Mainly active against gram negative bacteria • Mainly used to treat nosocomial infections: pneumonia in ITU, septicaemia • Can cause neuromuscular blockade • Also used in combination AmiNOglycosides
  • • Ototoxic esp. when used with furosemide • Nephrotoxic • Neuromuscular blockade ( dec. Acetylcholine release, can be managed by Ca gluconate, neostigmine) • Synergistic effect with beta-lactams • Antagonistic with CMC ADR: AmiNOglycosides
  • • Streptomycin: first anti-TB antibiotic from Strep. griseus • Neomycin: from Strep. fradiae (orally active) • Paromomycin: Strep. rimosus anti- amebic • Kanamycin: Strep. kanamyceticus, tx for bacillary dysentery AmiNOglycosides
  • • Amikacin: semi-synthetic, 1-N- amino-a-hydroxybutyrylkanamycin • Gentamicin: from Micromonospora purpurea (cream, ung.) • Tobramycin: most active nebramycins, obtained from Strep. Tenebrarius, useful for conjunctivitis AmiNOglycosides
  • • Netilmicin: 1-N-ethylsisomicin • Sisomicin • Spectinomycin: aminocyclitol antibiotic AmiNOglycosides
  • •Tetracycline is: A. An intermediate spectrum, bactericidal B. A broad spectrum, bacteriostatic C. A broad spectrum. Bactericidal D.An intermediate spectrum, bacteriostatic Board Questions
  • Tetracyclines • Broad spectrum, -static • Binds to 30s • Isolated from Streptomyces or synthetically prepared • Derivatives of “octahydronaphthacene” • Amphotheric and zwitterions • Can chelate metals
  • Classification of Tetracyclines • Short – Acting: ▫ Tetracycline ▫ Oxytetracycline • Intermediate Acting: ▫ Demelocycline ▫ Lymecycline • Long – Acting: ▫ Doxycycline ▫ Minocycline
  • •Tetracycline: most popular •Rolitetracycline: condensation product of tetracycline •Chlortetracycline: bright yellow color •Oxytetracycline •Methacycline Tetracyclines
  • •Demelocycline: 7-chloro-6- demethyltetracycline •Melocycline •Doxycycline: least phototoxic among TCNs •Minocycline: most potent tetracycline • Tigecycline: first glycylcycline Tetracyclines
  • Activity: Tetracyclines • Effective for Chlamydia, Mycoplasma, Pneumonia, Rocky mountain spotted fever, Lyme’s disease, Cholera, H. pylori
  • Structure of Tetracyclines
  • Tetracycline SE • Gastric distress • Yellowing of teeth • Bulging fontanel • Phototoxicity • Liver damage • Affects renal function
  • • Which of the following is used for leptospirosis and malaria? A. Metronidazole B. Euphorbia hirta C. Doxycycline D. Penicillin E. Dactinomycin Board Questions
  • • Class of antibiotics which has large lactone ring, has a ketone group and has glycosidically linked amino sugar: A. Penicillin B. Cephalosporins C. Aminoglycosides D.Macrolides Board Questions
  • Macrolides • Isolated from Actinomycetes • Binds 50s, -cidal at high dose • Chemical characteristics: ▫ Large lactone ring ▫ Ketone group ▫ Glycosidically linked amino sugars • Spectrum of activity: same with PCNs
  • Structure of Macrolides
  • Macrolides •Erythromycin •Erythromycin estolate: lauryl sulfate, Ilosone • Erythromycin lactobionate: erythromycin base is reacted with lactobiono-sigma-lactone • Clarithromycin: 6-methyl ether of erythromycin,
  • Macrolides •Azithromycin: semi-synthetic derivative of erythromycin, prototype of the azalides: • Dirithromycin lactobionate: more soluble prodrug of 9S- erythromycyclamine • Troleandomycin: a triacetyl derivative of oleandomycin
  • Macrolides: SE •GIT disturbances •Jaundice or cholestatic hepatitis •Thrombophlebitis • Inhibits cytochrome P450 • DI: Terfenadine and astemizole: arrhythmia
  • •Which of the following contains sulfur? A.Lincomycin B.Clindamycin C.Clarithromycin D. Penicilllin G Board Questions
  • Lincomycins •Lincomycin: contains a pyrrolidine nitrogen. •Clindamycin: 7-chloro-7-deoxy- lincomycin
  • Polypeptides • Describe as cyclic peptides • Most powerful bactericidal antibiotics characterized by presence of sever – CONH linkages • SE: neurotoxicity and nephrotoxicity
  • Polypeptides •Vancomycin: from Strep. orientalis DOC for Pseudomembranous colitis (PO) • ADR: “red-man” syndrome: flushing due to histamine release caused by rapid infusion
  • Polypeptides • Teicoplanin: Actinoplanes teichomyceticus • MOA: inhibitor of cell wall synthesis affecting peptidoglycan layer • Bacitracin: from Bacillus subtillis enhance activity with zinc • Polymyxin B: Bacillus polymyxa
  • Polypeptides • Colistin: Aerobacillus colistinus • Colismethane sodium • Gramicidin: from tyrorthricin, act as tunnelling molecule that act on the plasma membrane and result in the uncontrolled movement of ions across cell membrane leading to cell death. Isolated from Bacillus brevis
  • • Which of the following chemotherapeutic agents has a good penetrability into the cerebrospinal fluid? A. Cephalexin B. Chloramphenicol C. Streptomycin D. Tobramycin E. Gentamicin Board Questions
  • Unclassified Antibiotics •Chloramphenicol: with nitro group • DOC for typhoid fever • ADRs: gray-baby syndrome, blood dyscrasias
  • ADR of Chloramphenicol • Hemolytic anemia: G6PD deficient • Aplastic anemia • Gray-baby syndrome (cyanosis), blood dyscrasias • Inhibits CYP450
  • Unclassified Antibiotics •Novobiocin: topical use • Mupirocin: topical use • MOA: interference with RNA and protein synthesis • Quinupristin/Dalfopristin (30:70)
  • Unclassified Antibiotics • Linezolid: an oxazolidinedione that can prevent the formation of 70s ribosome by binding to the 50s subunit • Fosfomycin tromethamine
  • Some other antibiotics occasionally used • Co-trimoxazole • Chloramphenicol (typhoid fever, meningitis) • Colistin (resistant Pseudomonas) topical • Neomycin: GUT decontamination, topical
  • Antibiotics for PUD •Amoxicillin •Clarithromycin •Metronidazole (anti-protozoal) •Tetracycline
  • Drug of Choice • Listeria monocytogenes • Salmonella • Shigela spp. • Meningitis • ANSWER: A _ _ _ _ _ _ _ _ N Gram +
  • • Clostridium perfringens • Cause: ______ • Treponema pallidum • Cause: ______ • ANSWER: ____________ • Clue: aka Benzylpenicillin Drug of Choice
  • •MRSA •MRSA means _____________ •ANSWER: V__________ Drug of Choice
  • • for SURGICAL PROPHYLAXIS • ANSWER: Cefa____ injection • Reason: used because of high bone penetration and because it’s a good alternative to anti-staph penicillin in penicillin – allergic patients. Drug of Choice
  • • for Enterococcus • ANSWER: G__________ • for Chlamydia trachomatis • ANSWER: A__________ • for Nocardia and Pneumocystis pneumonia • ANSWER: Co__________ Drug of Choice
  • • for Clostridium tetani • ANSWER: V__________ • for Neisseria gonorrhea • ANSWER: Ceftriaxone and Cefixime • for Typhoid d/t Salmonella • ANSWER: Ceftriaxone First Line Agent/s
  • • in treating penicillin resistant pneumonococci • ANSWERS: Ceftriaxone, Cefotaxime and Vancomycin First Line Agent/s
  • • for systemic Pseudomonas aeruginosa • ANSWERS: ▫ Ticarcillin ▫ Piperacillin ▫ Ceftazidime ▫ Cefepime ▫ Tobramycin First Line Agent/s
  • • for Nocardia • ANSWER: M__________ • for Helicobacter pylori • ANSWER: T__________ • for Vibrio spp. • ANSWER: D__________ First Line Agent/s
  • • for Brucella • ANSWER: D_________ + G________ • for Helicobacter pylori, Viridans streptococci, Strep. agalactiae, Listeria meningitis, Campylobacter • ANSWER: _ E _ _ _ M I C I N First Line Agent/s
  • • Question: What are the two penicillin-derived drugs that are extended spectrum for Pseudomonas infections? (First line and Broadest spectrum) • Answers: ▫ First Line: Ticarcillin and derivatives ▫ Broadest spectrum: Piperacillin and derivatives with Tazobactam
  • •Question: What is the first line agent used to treat mixed intra- abdominal infections by Bacteriodes? •Answers: ▫ Cefoxitin
  • • Question: What is the first line agents used to treat Haemophilus influenzae? • Answers: ▫ Ceftriaxone ▫ Cefotaxime
  • • Question: How do you treat antibiotic induced enterocolitis d/t Staph. aureus or Clostridium difficile? • Answers: ▫ Vancomycin PO ▫ Why PO? Because it is poorly absorbed orally and will therefore be very active against Gram + bacteria in the intestine causing colitis.
  • •Most importance specie as a source of anti-microbial agents: A. Actinomyces B. Streptomyces C. Penicillium D.Streptococci E. Tropane alkaloids Board Questions
  • Name of the Drug SOURCE Streptomycin Streptomyces griseus Clavulanic acid Streptomyces clavugeris Thienamycin Streptomyces cattleya Erythromycin Streptomyces erythreus Lincomycin Streptomyces lincolnensis Chlortetracycline Streptomyces aureofaciens Neomycin Streptomyces fradiae Kanamycin Streptomyces kanamyceticus Gentamicin Micromonospora purpurea Oxytetracycline Streptomyces rimosus
  • Name of the Drug SOURCE Vancomycin Streptomyces orientalis Bacitracin Bacillus subtilis Gramicidin Bacillus brevis Chloramphenicol Streptomyces venezuelae Rifamycins Streptomyces mediterranei Griseofulvin Penicillium griseofulvum Amphotericin B Streptomyces nodosus Nystatin Streptomyces noursei Natamycin Streptomyces natalensis Tobramycin Micromonospora tenebrarius
  • Anti-viral Agents • Virus: smallest self-replicating organisms INFECTION PROCESS OF A VIRUS Adsorption  Entry  Uncoating  Transcription Translation  Assembly  Release Adsorption Entry Uncoating Transcription Translation Assembly Release
  • Classification of Viruses • Nucleic acid: DNA or RNA viruses • Viral morphology: helical or icosahedral • Site of replication: cytoplasm or nucleus • Coating: enveloped or non-enveloped • Serological typing: antigenic signatures • Cell type infected: B-lymphocytes or T- lymphocytes
  • TARGETS FOR ANTI-VIRAL DRUGS
  • TARGETS OF ANTIVIRALS 1. VIRAL ENVELOPE/CAPSULE • Primary Targets for antibodies
  • 1. VIRAL ENVELOPE/CAPSULE • Primary Targets for antibodies 2. ATTACHMENT • Receptors may be blocked (sialic acid derivatives, ligands or anti-receptor antibodies) • The process of production is poorly understood and kinetic parameters are not well defined. TARGETS OF ANTIVIRALS
  • 3. PENETRATION / UNCOATING • Uncoating is largely mediated by cellular enzymes, • Penetration, is often influenced by one or more virus proteins • For Influenza virus, inhibition of M2 protein prevents viral penetration by inhibiting membrane fusion. NAM – N-acetylmuramic acid Hemmaglutinin M2 Proteins PENETRATION UNCOATING TARGETS OF ANTIVIRALS 1. VIRAL ENVELOPE/CAPSULE • Primary Targets for antibodies 2. ATTACHMENT • Receptors may be blocked (sialic acid derivatives, ligands or anti-receptor antibodies)
  • 4. REPLICATION • Targets various polymerases (HIV) • Serve as polymerase substrates to terminate replication. (nucleoside analogues) ACYCLOVIR TERMINATION OF THE DNA/RNA STRAND • Most nucleoside analogues are Pro- drugs: requires viral polymerase, NOT cell polymerase TARGETS OF ANTIVIRALS 1. VIRAL ENVELOPE/CAPSULE 2. ATACHEMENT 3. PENETRATION/UNCOATING
  • Chemoprophylaxis: Adamantanamines • MOA: prevent viral uncoating and interferes viral assembly • Amantadine: blocks viral ion channel M2 protein • Rimatadine: methylated- amantadine
  • Chemoprophylaxis: Neuraminidase inhibitors • Sialic acid analogs • Zanamivir: Bronchospasms • Oseltamivir : N & V
  • • Important cytokines that possess antiviral, immunomodulating and anti-proliferative action • MOA: inhibition of viral penetration or uncoating, synthesis of mRNA, translation of viral proteins, assembly and release Chemoprophylaxis: Interferons
  • • Three classes of interferons – α , β, γ • Indication: Venereal warts (Condyloma acuminatum), chronic hepa B and C, Kaposis sarcoma, MS • PEG – Interferon: 40 kDa, advantage of sustained delivery and reduced clearance of interferon Chemoprophylaxis: Interferons
  • • α and β interferons are produced by all the cells in response to viral infections. Effective against HBV, HCV and HPV. • γ interferons are produced only by T lymphocyte and NK cells in response to cytokines – immune regulating effects • γ has less anti-viral activity compared to α and β interferons Chemoprophylaxis: Interferons
  • Nucleoside antimetabolites • Inhibitors of DNA polymerase • Reverse transciptase inhibitors • Miscellaneous (Ribavirin): used for sever LRTI cause by RSV in carefully selected hospitalized infants and young children
  • DNA Polymerase inhibitors •Idoxuridine: iodinated analog of thymidine, non-selective, tx of herpes simplex keratitis •Trifluridine: fluorinated analogue of thymidine, tx of primary keratoconjunctivitis and recurrent epithelial keratitis due to HSV 1 and 2
  • DNA Polymerase inhibitors •Vidarabine: 2’epimer of natural adenoside, broad spectrum, alternative for idoxuridine •Cytarabine: MOA: blocks cellular utilization of deoxycytidine, hence inhibiting the replication of viral DNA
  • DNA Polymerase inhibitors: Acyclovir Congeners •Acyclovir (nucleoside analog of 2’deoxyguanosine) • and Valacyclovir (L-valyl ester prodrug): DOC for Varicella zoster, chicken pox
  • • Ganciclovir: Analogue of acyclovir with an additional HYDROXYMETHYL GROUP on the acyl side chain. • tx and supression of sight threatening CMV retinitis in immunocompromised patients DNA Polymerase inhibitors: Acyclovir Congeners
  • •Famciclovir: diacetyl prodrug of penciclovir •Penciclovir: tx of recurrent Herpes labialis. used only topically whereas Famciclovir can be administered orally. DNA Polymerase inhibitors: Acyclovir Congeners
  • DNA Polymerase inhibitors • Cidofovir: monophosphate nucleotide analogue of dCTP; tx of CMV retinitis in AIDS patient. AE: renal impairment • Foscarnet: 2nd line drug for the treatment of CMV retinitis in AIDS patients; trisodium phosphonoformate: organic analogue of inorganic pyrophosphate
  • DNA Polymerase inhibitors • Adefovir dipivoxil: DOC for chronic Hepatitis B • Ribavirin: a guanosine analog, inhibits RNA polymerase and reverse transcriptase. DOC for RSV bronchiolitis
  • Board Questions • Drugs used for herpes virus infection include the following, except: A. Oseltamivir B. Foscarnet C. Ganciclovir D. Idoxuridine E. Aciclovir
  • Reverse Transcriptase Inhibitors •Zidovudine (AZT): a thymidine analogue; SAR: 3’ azido group prevents the formation of 5’3’- phosphodiester bond, causing DNA termination • recommended for the management of adult patients with symptomatic HIV infection with history of PCP
  • Reverse Transcriptase Inhibitors • Didanosine: a guanine analog, recommended for AZT intolerant advanced HIV infection • Zalcitabine: cytosine analog, combined with AZT for the treatment of advance HIV infection
  • Reverse Transcriptase Inhibitors • Lamivudine: contains sulfur atom instead of a methylene group • Stavudine: thymidine analog. ADR: peripheral neuropathy
  • Agents for HIV infection • HIV – Vaccine ▫ Generally safe and elicit a protective immune response ▫ Stimulate both cellular and humoral immunity ▫ Protect components against all major HIV subtypes ▫ Induce long lasting protection ▫ Induce local immunity ▫ Practical for worldwide delivery and administration
  • Agents for HIV infection • Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ▫ Nevirapine ▫ Delaviridine ▫ Efavirenz: widely use NNRTIs •Common side effect: RASHES
  • Agents for HIV infection •HIV Protease inhibitors ▫ Saquinavir ▫ Indinavir ▫ Ritonavir ▫ Amprenavir ▫ Nelfinavir •Common side effect: Weight gain, dyslipidemia, hyperglycemia
  • New agents for HIV infection • HIV entry inhibitors • Chemokine Receptor binders • Inhibitors of GP41 Fusion activity • Integrase inhibitors (Raltegravir) • siRNA • CCR5 & CXCR4 • T20 (Pentafuside)
  • Anti-neoplastic Agents • Drugs intended for the treatment of cancer • Cancer: are abnormal cells characterized by tumors which are then characterized as malignant. • Two types of tumors: ▫ Benign: non-cancerous ▫ Malignant: cancerous • One gram of tumor is equivalent to _____________
  • • A very common adverse reaction of alkylating agents used in the treatment of cancer: A. Bulging fontanel B. Steven Johnson’s Syndrome C. Mydriasis D. Ataxia E. Alopecia Board Questions
  • COMMON SIDE EFFECTS ASSOCIATED TO ANTICANCER AGENTS
  • Alkylating agents (Nitrogen Mustards) • Agents that replace hydrogen with an alkyl group (by substitution). Forms adducts causing DNA strand breakage. • Thiotepa: mainstay therapy for solid tumors when followed by autologous bone marrow transplantation • Mechlorethamine: a dialkylating agent, DOC for Hodgkin’s disease • Ifosfamide: for germ cell testicular cancer
  • Alkylating agents (Nitrogen Mustards) • Busulfan: “causes sulfur stripping” • Cyclophosphamide: cell cycle non- specific, phosphoramide mustard (major metabolite) • Melphalan: for multiple myeloma • Chlorambucil: first line agent for chronic lymphocytic leukemia and macroglobulinemia • Bendamustine (Merck Manual,table 124-3)
  • •Mechanism of action: •Establishes cross-links within and between DNA strands Alkylating agents (Organoplatinum)
  • •Cisplatin: most reactive and most effective in platinating DNA •Carboplatin: administered with 1,1-cyclobutane-dicarboxylate to reduce toxicity •Oxaliplatin: activated in low- chloride environment, not recognized by MMR Alkylating agents (Organoplatinum)
  • • Alkylates DNA with restricted uncoiling and replication of strands. • Lomustine: first line for metastatic brain tumor and second line for recurring Hodgkin’s disease • Carmustine: used for brain tumors (can penetrate BBB) Alkylating agents (Nitrosoureas)
  • Alkylating agents • Procarbazine: for Hodgkin’s lymphoma • Dacarbazine and Temozolomide: form DNA adducts • Altretamine: involves in hydroxylation of methyl group • Streptozocin: useful in inducing hyperglycemia on animal model; from Strep. achromogenes subsp. Strepzoticus
  • • Which of the following antineoplastics is not considered an anti-metabolite? A. Cytarabine B. Methotrexate C. Etoposide D. Thioguanine E. Fluorouracil Board Questions
  • Anti-metabolites • Compounds closely related in structure to a cellular precursor (N- base), act as “imposter” that is capable of preventing the proper use of these natural cellular precursor • MOA: prevention of biosynthesis or use of normal cellular metabolites by enzyme inhibition
  • Anti-metabolites (Folates) • Folates (anti-folates): designed to interact at cofactor sites for enzymes involved in the biosynthesis of nucleic acid bases. • Methotrexate: first drug to produce substantial remissions in leukemia esp. ALL binds to dihydrofolate reductase and interferes with TS • Pemetrexed: a pyrrolopyrimidine analog. MOA: inhibition of TS
  • Anti-metabolites (Folates) • Trimetrexate: non-classical folate antagonist that is structurally similar to MTX. Inhibits enzyme dihydrofolate reductase and has been approved for the treatment of Pneumocystis carinii pneumonia in patient with HIV/AIDS. • Hydroxyurea: MOA: inhibition of ribonucleotide reductase
  • •6-mercaptopurine: (blokcks de novo purine synthesis) primary treatment for acute leukemia together with 6- thioguanine • MOA: incorporation of the triphosphate metabolite into DNA/RNA Anti-metabolites (Purine)
  • •Fludarabine: Useful of chronic lymphocytic leukemia and non- Hodgkin’s lymphoma. Inhibits DNA synthesis and inhibits ribonucleotide reductase. Anti-metabolites (Purine)
  • •Cladribine: a deoxyadenosine analog for hairy cell leukemia. MOA: incorporation into DNA causing inhibition of DNA chain extension and inhibition of DNA synthesis and function. Inhibits ribonucleotide reductase Anti-metabolites (Purine)
  • • Vidarabine • Clofarabine: Inhibits DNA synthesis • Pentostatin: MOA: inhibition of adenosine deaminase  increase dATP (cytotoxic to lymphocytes). • Nelarabine and Pentostatin: inhibits DNA synthesis Anti-metabolites (Purine)
  • • 5-FU: palliative treatment of carcinoma of the breast, colon, pancreas, rectum and stomach. MOA: inhibition of TS by the deoxyribose monophosphate metabolite. Anti-metabolites (Pyrimidine)
  • • Floxuridine (FUDR): a fluopyrimidine deoxynucleoside analog used to treat GI adenocarcinoma metastatic to the liver. MOA: converted to 5-FU  inhibition of TS disrupting DNA synthesis, function and repair. Anti-metabolites (Pyrimidine)
  • • Capecitabine: a fluoropyrimidine carbamate prodrug of 5-FU used for metastatic breast and colorectal cancer. MOA: converted to 5-FU by thymidine phosphorylase  esterase activity to hydrolyze the carbamate moiety and deamination. Anti-metabolites (Pyrimidine)
  • •Gemcitabine: a fluorine-substituted deoxycytidine analog, inhibit DNA synthesis and function via DNA chain termination, a potent radiosensitizer. • DOC for locally advanced or metastastic adenocarcinoma of the pancreas; with cisplatin. DOC for inoperable locally advanced or metastatic NSCLC. Anti-metabolites (Pyrimidine)
  • • Cytarabine: a cytosine arabinoside from Cryptothetya crypta treatment for acute agranulocytic leukemia. Activated into ara-CTP which is then incorporated to DNA chain causing chain termination and inhibition of DNA synthesis • 5-Azacytidine, Decitabine, Tegafur Anti-metabolites (Pyrimidine)
  • •The following antibiotic possess clinically useful anti – malignant property, except: A. Streptomycin B. Daunorubicin C. Mitomycin D. Plicamycin E. Bleomycin Board Questions
  • Antineoplastic - Antibiotic • Actinomycins: Dactinomycin/ Actinomycin D • Anthracycline: Doxorubicin, Daunorubicin, Idarubicin, Epirubicin and Valrubicin • Glycopeptide: Bleomycin
  • Antineoplastic – Antibiotic (Actinomycin) • Dactinomycin: from Strep. parvilus, tx of rhabdomyosarcoma and Wilm’s tumor in children, lifesaving tx for women with choriocarcinoma resistant to MTX • MOA: binds non-covalently to double stranded DNA by partial intercalation between the adjacent G-C bases resulting to inhibition of DNA function.
  • Antineoplastic – Antibiotic (Anthracyclines) • With planar oxidized anthracene nucleus fused to a cyclohexane ring connected via glycosidic bond with amino sugar • MOA: association of the drug with DNA resulting from intercalation of the planar ring system reinforced by auxiliary binding of amino sugar.
  • Antineoplastic – Antibiotic (Anthracyclines) •Daunorubicin: Inhibits topoisomerase II. Isolated from Strep. peucetius useful for non-lymphocytic and lymphocytic leukemia. •Doxorubicin: Inhibits topoisomerase II. Isolated from Strep. peucetius var. caesius doxorubicinol = cardiotoxic
  • Antineoplastic – Antibiotic (Anthracyclines) • Idarubicin: lacks 4-methoxy group (increase inhibition of topoisomerase II) and terminal side chain; tx of blast phase chronic myelogenous carcinoma, less cardiotoxic than doxorubicin • Epirubicin: 4’-epimer of doxorubicin (less cardotoxic) topoisomerase II inhibiotr
  • Antineoplastic – Antibiotic (Anthracyclines) •Valrubicin: for BCG-refractory carcinoma of the urinary bladder •Mitoxantrone: MOA: inhibits topoisomerase II and cause DNA strand breakage; can tint the urine blue.
  • Antineoplastic - Antibiotic •Bleomycin: a glycopeptide antibiotic from Strep. verticillus, palliative treatment of squamous cell carcinoma, produce ROS  causing single strand breakage. Lacks bone marrow toxicity • SE: Pulmonary fibrosis
  • Antineoplastic - Antibiotic •Mitomycin C: “Bioreductive alkylating agent”; from Strep. Caespitosus •Plicamycin: first line for Paget’s diease
  • Plant Products (Epipodophyllotoxin) • From Mandrake/Mayapple • Inhibits microtubule function by acting on topoisomerase II  DNA strand breakage • Etoposide: for testicular and small cell lung cancer • Teniposide: for acute lymphoblastic leukemia (more potent inhibitor of topoisomerase II)
  • • inhibitors of topoisomerase I • from Camptotheca acuminata •Irinotecan: a semi-synthetic analogue of camptotechin) •Topotecan: Microscopic hematuria can be seen Plant Products (Camptothecins)
  • •Vinca alkaloids: usually obtained from Vinca rosa/Catharantus roseus (Periwinkle); bind to tubulin disrupting formation and function of the mitotic spindle by arresting mitosis by inhibiting the polymerization of microtubules Plant Products (Vinca alkaloids)
  • • Vincristine and vinblastine differ only in the group attached to the dihydroindole nitrogen, vincristine (formyl) and vinblastine (methyl). Plant Products (Vinca alkaloids)
  • • Vinblastine: part of ABVD regimen for Hodgkin’s lymphoma. Extravasation is seen (most of the vincas) managed by the use of hyaluronic acid and heat. • Vincristine: useful for Hodgkin’s lymphoma • Vinorelbine: semi-synthetic for NSCLC Plant Products (Vinca alkaloids)
  • • Taxanes: from Pacific Yew Tree (Taxus brevifolia or T. baccatta). Administered with Cremophor EL and ethanol (due to poor water solubility) • MOA is same with the vincas (binds to β- tubulin and cause cell death) • Paclitaxel: highly protein bound, can cause bradycardia. MOA: promotes assembly of microtubules Plant Products (Taxanes)
  • •Docetaxel: promotes assembly of microtubules; a semi-synthetic, SE includes reversible fluid retention •Ixabepilone: semisynthetic amide analog of epothilone B that is isolated from the myxobaterium Sorangium cellulosum Plant Products (Taxanes)
  • Protein (Tyrosine) Kinase inhibitors • is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that add a phosphate (PO4) group to a protein or other organic molecule. Phosphate groups can turn a protein off.
  • Protein (Tyrosine) Kinase inhibitors • Erlotinib: inhibits epidermal growth factor receptor. SE: Acne. diarrhea • Imatinib: inhibits BCR-ABL kinase and c-kit kinase • Lapatinib: inhibits Her2/neu activity • Sorafenib: inhibits intracellular and cell surface kinase like VEGFR
  • Protein (Tyrosine) Kinase inhibitors • Sunitinib: inhibits receptor tyrosine kinases • Dasatinib • Geftinib
  • Hormones • Bicalutamide and Flutamide: androgen receptor antagonist used for tx of advance prostate cancer • Fluvestrant: binds to estrogen receptor used for the treatment of metastatic breast cancer • Leuprolide acetate: inhibits gonadotropin secretion for prostate cancer.
  • Hormones • Megestrol acetate: advanced breast or endometrial cancer a progesterone antagonist • Tamoxifen: Selective Estrogen Receptor Modulators (SERMs); an anti- estrogen and has triphenylethylene structurenon-steroidal agent for advanced breast cancer
  • Hormones • Raloxifene: SERMs which is a benzothiophene derivative • Goserelin: palliative treatment of advanced prostate carcinoma, breast cancer and endometriosis • Mitotane: inoperable adrenal cortical carcinoma • Dromostanolone: pallative treatment of metastatic breast cancer
  • Hormones • Testolactone: palliative treatment of advanced or disseminated breast cancer • Aminoglutethimide: treatment for Cushing’s syndrome • Toremifene: for metastatic breast cancer • Other agents includes: Nilutamide, Estramustine, Triptoralen
  • Hormones: Aromatase Inhibitors • Blocks conversion of androgen to estrogen • Exemestane: non-steroidal aromatase inhibitor; for hormone dependent breast cancer • Letrozole (non-steroidal aromatase inhibitor) and anastrazole: for locally advanced or metastatic breast carcinoma
  • Immunotherapy • Interferon alfa – 2A: useful for patient 18 y/o or older for hairy cell leukemia and chronic myelogenous leukemia; has anti-proliferative effect • Interferon alfa – 2B: indicated for hairy cell leukemia and treatment of malignant melanoma. • Interferon alfa – n3
  • Immunotherapy •Aldesleukin: stimulates T-cell growth and regulation, proliferation and immunoglobulin production in B lymphocytes and macrophage activity enhancement •Denileukin •BCG
  • Monoclonal antibody “mab” • Product of rDNA techonology •Alemtuzumab: Binds to B and T cells •Bevacizumab: Binds to vascular endothelial growth factor •Gentuzumab: Binds to CD33 on leukemic cells
  • Monoclonal antibody “mab” • Ibritumomab tiutexan, Iodine - 131 tositumomab, Tositumomab: Binds to CD 20 on lymphoid cells • Rituximab: a genetically engineered chimeric monoclonal antibody against CD20 antigen on malignant B lymphocyates
  • Monoclonal antibody “mab” •Trastuzumab: for breast cancer which selectively binds with high affinity to the extracllular domain of human epidermal growth factor 2 protein and neu receptor
  • Proteosome inhibitor •Bortezomib •Vorinostat
  • Miscellaneous •Arsenic trioxide: tx of acute promyelocytic leukemia •Bexarotene: tx for cutaneous T- cell lymphoma in patient refractory prior to systemic therapy •Azathioprine: adjunct therapy to prevent rejection of renal heterotransplants
  • Miscellaneous •Asparaginase: enzyme from E. coli. MOA: reduces asparagine in plasma making it unavailable for leukemic cells (Pegasparagase: modified L-asparaginase
  • Miscellaneous • Sargamostim: a GM-CSF from Saccharomyces cerevisiae or E. coli. Use to promote bone marrow recovery in patient underwent autologus bone marrow transplantation • Temsirolimus
  • Cytoprotectives • Counteract side effects of other antineoplastic agents. • Mesna: indicated for ifosfamide-induced hemorrhagic cystitis • Amifostine: reduce accumulative toxicity from cisplatin and xerostoma • Dexrazoxane: potent intracellular chelating agent, reduce cumulative toxicity with doxorubicin
  • Matching Type 1. Terbinafine 2. Itraconazole 3. Caspofungin 4. Alendronate 5. Mycophenolate A. Squalene monooxygenase B. Sterol 14a-methylase C. 1,3 β glucan synthase D. Farnesyl diphosphate transferase E. IMP dehydrogenase
  • Matching Type 1. Cilastatin 2. Oseltamivir 3. Atorvastatin 4. Etodolac 5. Entacapone A. Viral neuraminidase B. Renal dehydropeptidase C. COMT D. HMG CoA reductase E. Prostaglandin endoperoxide synthase
  • Matching Type 1. Physostigmine 2. Sildenafil 3. EMB 4. Miglitol 5. Acarbose A. α-amylase B. α-glucosidase C. Arabinosyl transferase D. Phosphodiesterase inhibitor E. Acetylcholinesterase inhibitor
  • Matching Type 1. Streptomycin 2. Chlortetracyline 3. Erythromycin 4. Gentamicin 5. Thienamycin A. Streptomyces erythreus B. Streptomyces cattleya C. Micromonospora purpurea D. Streptomyces griseus E. Streptomyces aureofaciens
  • Matching Type 1. Vancomycin 2. Nystatin 3. Amphotericin B 4. Griseofulvin 5. Chloramphenicol A. Streptomyces noursei B. Streptomyces venezuelae C. Penicillium griseofulvum D. Streptomyces nodosus E. Streptomyces orientalis
  • Matching Type 1. D-Cyloserine 2. Teicoplanin 3. Daptomycin 4. Quinupristin 5. Polymyxin B A. Streptomyces pristinaespiralis B. Streptomyces garyphalus C. Actinoplanes teichomyceticus D. Bacillus polymyxa E. Streptomyces roseosporus