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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)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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.
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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:
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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.
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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.
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
• 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
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
•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
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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.
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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 :
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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
 
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-)
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ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)
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ORGANIC CHEMISTRY COMPLETE (PRE-BOARD REVIEW 2014)

  • 1. Refresher Course on Organic Chemistry and Organic Medicinal Chemistry Mr. Jan Dominique R. Lapig, RPh. April – May 2014
  • 3. The Study of Chemistry What is Chemistry? Chemistry is the study of the properties and behavior of matter. Science of the composition of matter and changes in composition it may undergo either spontaneously or because of intentionally established environmental condition. Matter – anything that occupies space and has mass.
  • 4. 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)
  • 6. 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.
  • 8. 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
  • 9. Separation of Mixtures Mixtures can be separated by physical means. –Filtration –Chromatography –Distillation Classification of Matter
  • 11. 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
  • 12. 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
  • 13. 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
  • 14. 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.
  • 15. 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
  • 16. 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
  • 17. 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
  • 18. Physical and Chemical Changes Properties of Matter
  • 19. Physical Properties of Drug Molecule • Physical States: –Amorphous solid –Crystalline solid –Hygroscopic solid –Liquid –Gas
  • 20. 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
  • 21. Physical Properties of Drug Molecule • Boiling point: temperature at which the vapor pressure of the liquid is equal to the atmospheric pressure
  • 22. 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.
  • 23. 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
  • 24. 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
  • 25. 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
  • 27. 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
  • 28. 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.
  • 29. 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?
  • 30. 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+]
  • 31. 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?
  • 32. 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-]
  • 33. 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.
  • 34. 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
  • 35. 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
  • 36. 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
  • 37. 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.
  • 41. 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
  • 42. 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
  • 43. 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
  • 44. 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
  • 45.  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
  • 46. 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
  • 48. 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.
  • 49. 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.
  • 50. 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
  • 51. 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
  • 52. 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
  • 53. 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
  • 54. 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
  • 55. 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)
  • 56. 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.
  • 57. 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.
  • 58. 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.
  • 59. 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.
  • 61. 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.
  • 62. 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
  • 63. 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.
  • 65. 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
  • 66. Practice Set • Given: Boron, Nitrogen, Phosphorus • Find the following: ▫ Electronic configuration ▫ Orbital diagram ▫ Core configuration ▫ Graphical diagram ▫ Valence number
  • 68. INORGANIC CHEMISTRY  is the branch of chemistry concerned with the properties and behavior of inorganic compounds. Inorganic vs. Organic Chemistry
  • 70. ORGANIC CHEMISTRY  is the branch of chemistry which deals with carbon- containing compounds. Inorganic vs. Organic Chemistry
  • 71. 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).
  • 72. 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
  • 73. 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
  • 75. Carbon: The Chemical Basis for Life  From the Latin word “carbo” meaning charcoal.  Group __ element  IUPAC classification: Group __ element  Symbol: ___  Atomic no.: ___
  • 76.  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
  • 78.  Fullerene  antioxidant  Amorphous Carbon  adsorbent Allotropes of Carbon
  • 79.  Crystal Structure: Hexagonal  Electronic configuration Carbon Facts
  • 80. 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.
  • 82. 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.
  • 83.  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
  • 85. s-orbital p-orbitals bond side ways overlap end to end overlap of orbitals leads to σ -bond σ -bond HYBRIDIZATION
  • 86. Types of Carbon Hybrid Orbitals  sp3 hybrid or tetrahedral hybrid  sp2 hybrid or trigonal planar hybrid  sp hybrid or linear hybrid
  • 87. Types of Carbon Hybrid Orbitals  sp3d hybrid  sp3d2 hybrid
  • 88. 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
  • 89. 109.50 sp3 hybridized carbon 4 equivalent C-H bonds (s-bonds) All purely single bonds are called s-bonds Methane is Tetrahedral
  • 90. sp2 hybrid or Trigonal hybrid  *C6 1s2 2s1 2px1 2py1 2pz1 pure AO  (2sp2)1(2sp2)1 (2sp2)1 2pz1 hybrid AO
  • 91. sp hybrid or Linear hybrid  *C6 1s2 2s1 2px1 2py1 2pz1 pure AO  (2sp)1(2sp)1 2py1 2pz1 hybrid AO
  • 93. 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
  • 94.  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
  • 99. 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.
  • 100.  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:
  • 101.  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:
  • 104. 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.
  • 105. Hydrocarbon Derivatives • An almost unlimited number of carbon compounds can be formed by the addition of a functional group to a hydrocarbon.
  • 107. Type or General Formula Class Type formula Alkane CnH2n+2 Alkene CnH2n Alkyne CnH2n-2 Cycloalkane CnH2n Cycloalkene CnH2n-2 Cycloalkyne CnH2n-4
  • 109. 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
  • 110. Who discovered the structure of benzene? Friedrich August Kekule
  • 111. Phenol Ar-OH Ether R-O-R Aldehyde R- CHO Ketone R-CO-R Type or General Formula
  • 112. 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
  • 113. 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
  • 114. Nitroso R-N = O Nitrile (cyanide) R-C  N Imine Imide Type or General Formula
  • 115. Diazo Hydrazino R-NHNH2 Mercaptan (thiol) R-SH Thioether R-S-R Enol Type or General Formula
  • 116. 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
  • 117. What is the type formula for ethers? A. RH B. RX C. ROR D. RCHO E. RCOOR PACOP QUESTION
  • 118. The compound with the formula CH3CH2COCH2CH3 is a/an: A. Ketone B. Aldehyde C. Carboxylic acid D. Ether E. Ester PACOP QUESTION
  • 119. The structure shown below is: C C C C C C H H H H HH =
  • 120. Naphthalene Anthracene Phenanthrene The structure shown below is:
  • 124. Isomers • compounds having the same molecular formula but different structural formulas.
  • 125. 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.
  • 126. Types of Structural Isomers • Chain isomers or skeletal isomers • Positional isomers • Functional isomers ▫ Tautomers
  • 127. • Chain/Skeletal isomers ▫ Compounds that differ in the arrangement of carbons. Types of Structural Isomers
  • 128. • Positional isomers ▫ Differ in the position of a non carbon group. Types of Structural Isomers
  • 129. • Functional Isomer ▫ Differ in the functional group. Types of Structural Isomers
  • 130. •2-pentanol and 3-pentanol are: A. Functional isomers B. Positional isomers C. Chain isomers D.Optical isomers E. Stereoisomers PACOP QUESTION
  • 131. •2 - pentanol ▫ CH3CHOHCH2CH2CH3 •3 - pentanol ▫ CH3CH2CHOHCH2CH3 Answers:
  • 132. 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.
  • 134. 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.
  • 136. • Diastereomers ▫ Stereoisomers that are non – superimposable and non – mirror images of each other. Types of Configurational Isomers
  • 138. • 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
  • 139. trans vs. cis isomers
  • 141. •Enantiomers differ from one another in: A.Spatial configuration B.Rational formula C.Ion-pair formation D.Photoelectric effect PACOP QUESTION
  • 142. R vs. S Configuration Cahn-Ingold-Prelog system Determines R or S designation of enantiomers
  • 144. Chiral or Asymmetric Center • Chiral or Asymmetric Center ▫ a molecule which contains a carbon to which four different groups are attached.
  • 145. Identify which is the Chiral carbon
  • 147. Tautomers • Isomers that differ from each other in the position of hydrogen atom and double bond.
  • 148. •Propanone and 1 – propen-1-ol are considered; A. Positional isomers B. Configurational isomers C. Tautomers D.Enantiomers E. Chain isomers PACOP QUESTION
  • 150. • They are diastereomers that differ only in the position of moieties at the first carbon atom. Anomers
  • 151. Meso Compound • one whose molecules are superimposable on their mirror images, even though they contain chiral centers.
  • 152. Racemic Mixture • mixture of equimolar concentration of enantiomers in a solution.
  • 154. IUPAC System Nomenclature •STEP 1: Name the Parent name. • Select the longest continuous chain. Hexane
  • 155. •STEP 2: Number the Cs in the chain, from either end, such that the substituent are given the lowest #s possible. IUPAC System Nomenclature
  • 156. • 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
  • 157. • 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
  • 158. 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
  • 162. 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 –
  • 163. • 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
  • 164. • 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
  • 165. • What is the type formula of the chemical methoxyethane? A. RCHO B. RCOOH C. RCOOR D. RCOR E. ROR PACOP QUESTION
  • 167. Mechanism of Reaction: the detailed course of overall reaction. • Sequence of steps • Details of electron movement • Bond breaking • Bond making • Timing
  • 168. • 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.
  • 169. Types of Bond Cleavage • Homolytic Cleavage ▫ Characterized by homolytic fission of bonds and the formation of free radicals.
  • 170. • Heterocyclic Cleavage ▫ Characterized by heterocyclic fission and the formation of charged species. Types of Bond Cleavage
  • 171. Types of Reagents •1. Nucleophiles (Nu:) ▫ electron-rich species ▫ electron pair donor ▫ attack positions with + charge or low electron density
  • 172. •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
  • 174. Types of Organic Reactions • Substitution reaction • Addition reaction • Elimination reaction • Rearrangement reaction • Oxidation • Reduction
  • 179. Oxidation • increase in oxygen • Increase in electron • decrease in hydrogen
  • 180. Reduction • increase in hydrogen • decrease in electron • decrease in oxygen
  • 183. Atomic Bonds 1. Ionic bonding 2. Covalent bonding 3. Hydrogen bonding or bridging) 4. Van der Waals (London forces)
  • 184. Ionic Bonding ▫ electrostatic interaction resulting from the transfer of an electron during the compound formation. Atomic Bonds
  • 185. Covalent Bonding ▫ is the attractive force that exists between two chemicals entities due to their sharing a pair of electrons. Atomic Bonds
  • 186. 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
  • 187. 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
  • 188. 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
  • 189. 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
  • 190. 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
  • 191. 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
  • 192. 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
  • 193. 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
  • 194. •Upon storage, alcohols are stable •In vivo, alcohols may undergo ▫ Oxidation ▫ Glucoronidation ▫ Sulfation Alcohols
  • 195. 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
  • 196. • 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
  • 197. Important Alcohols and Phenols • Methanol • Ethanol • Isopropyl alcohol • Cholesterol • Glycerol • Ethylene glycol • Phenol • Cresol • Resorcinol • Hexylresorcinol • Menthol • Geraniol • Glucose
  • 198. 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
  • 199. 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
  • 200. 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
  • 201. Important Aldehydes • Formaldehyde • Acetaldehyde • Chloral hydrate • Benzaldehyde • Cinnamaldehyde • Vanillin • Citral
  • 202. 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
  • 203. 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
  • 204. • 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
  • 205. • 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
  • 206. Carboxylic acids • Lipid soluble ▫ LMW carboxylic acids are water soluble (Na, K salts) • Common reactions are: ▫ Salt formation with bases ▫ Esterification ▫ Decarboxylation
  • 207. • On the shelf, carboxylic acids are very stable • In vivo, carboxylic acids undergo ▫ Conjugation with glucoronic acid, glycine and glutamine ▫ Beta oxidation Carboxylic acids
  • 208. Important Carboxylic acids • Salicylic acid • Citric acid • Lactic acid • Tartaric acid • Benzoic acid • ASA • PABA
  • 209. 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
  • 210. 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
  • 211. Important Amides •Acetanilide •Niacinamide or nicotinamide •Sulfanilamide
  • 212. Part III: Organic Medicinal Chemistry Mr. Jan Dominique R. Lapig, RPh April – May 2014
  • 213. Medicinal Chemistry “…let’s make a change on an existing compound or synthesize a new structure and see what happens…”
  • 214. What is Medicinal Chemistry? • Medicinal Chemistry is a chemistry-based discipline, involving the aspects of biological, medical and pharmaceutical sciences.
  • 215. What is Medicinal Chemistry? • Medicinal Chemistry devoted to the discovery and development of new agents for treating diseases. - Wilson and Gisvold’s 12th ed.
  • 216. Synthetic Chemistry • involves changes designed to transform a starting substance with a particular set of properties.
  • 217. 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
  • 218. 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
  • 219. • 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
  • 220. •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
  • 221. 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.
  • 222. 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).
  • 223. 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”
  • 224. 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
  • 225. 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
  • 226. 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
  • 227. • 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:
  • 228. • 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:
  • 229. •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:
  • 230. •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:
  • 231. 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
  • 232. • 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
  • 233. • 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
  • 234. ▫ 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
  • 236. Life Cycle for new drug :
  • 238. 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.
  • 239. 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.
  • 240. 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
  • 241. 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.
  • 242. 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
  • 243. 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
  • 244. 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.
  • 245. Historical Timeline: Elixir 1906 1937 No Regulatory control for Drug safety Sulfanilamide disaster Federal Food and Drug Act passed 1938 1961 Thalidomide crisis
  • 247. 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.
  • 248. 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
  • 249. • 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:
  • 251. •Biotechnology techniques a. Recombinant DNA b. Mutagenesis- site directed that fuse cell lines Discovery & Development of Organic Medicinal Chemicals:
  • 252. 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
  • 253. •ANIMAL SOURCES: Glandular products from animals are used, such as insulin and thyroid. Sources of Drugs
  • 254. • 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
  • 255. • 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
  • 256. 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.
  • 257. 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:
  • 258. 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:
  • 259. 1. CHEMICALLY DERIVED STEMS  PREFIX cef- (cephalosphorins) cefotetan, cefixime  INFIX -nab- (cannabinols) dronabinol, tinabinol  SUFFIX –azoles (antifungal imidazole) ketoconazole, fluconazole, itraconazole. Naming of Drugs
  • 260. 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
  • 261. 3.COMBINATION STEMS e.g. *–olol (beta blockers): timolol, atenolol, metoprolol *–profen (ibuprofen type; anti- inflammatory/analgesic agents): ibuprofen, ketoprofen Naming of Drugs
  • 262. 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.
  • 263. 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.
  • 264. 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
  • 265. 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.
  • 266. 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
  • 267. •Site-specific prodrugs: where carrier acts as transporter of the active drug to a specific targeted site. Prodrug
  • 268. 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 _______.
  • 269. 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 _______.
  • 270. • 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
  • 271. 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)
  • 272. 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
  • 273. 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
  • 274. BIOLOGICAL EFFECT OF A DRUG • result of an interaction between the drug substance and functionally important cell receptors or enzyme systems.
  • 275. 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.
  • 276. 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.
  • 277. • 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:
  • 278. Physicochemical Properties • Polarity • Acidity/Basicity • Dissolution • Particle size and Surface Are • Salt formation • Polymorphism • Chirality • Hydrates • Complex formation • Viscosity
  • 279. 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
  • 280. 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
  • 281. 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)
  • 282. 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
  • 283. 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
  • 286. 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).
  • 287. 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.
  • 288. 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
  • 289. Consider the following: •Indomethacin pKa = 4.5 well absorbed in ____________. •Ephedrine pKa = 9.6 well absorbed in _____________.
  • 290. Forces of Attraction • Van der Waals • Dipole-dipole bonding • Ionic bonding • Ion-dipole binding • Covalent bond • Reinforce ionic • Hydrogen bond • Hydrophobic bond
  • 291. Physicochemical Properties • Polarity • Acidity/Basicity • Dissolution • Particle size and Surface Area • Salt formation • Polymorphism • Chirality • Hydrates • Complex formation • Viscosity
  • 292. 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.
  • 293. 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
  • 294. 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
  • 295. 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
  • 296. 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)
  • 297. 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
  • 298. 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
  • 299. Tissue Depot • The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots. • Barbiturates activity
  • 300. Importance of Drug Metabolism • The basic premise: • Lipophillic Drugs  Hydrophillic Metabolites (Not Excreted) (Excreted) • Generally pharmacologically inactive and • Non-toxic metabolites
  • 301. 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.
  • 302. 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 ____________.
  • 303. 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.
  • 304. Importance of Drug Metabolism •Termination of Drug Action • Bioinactivation • Detoxification • Elimination
  • 308. Importance of Drug Metabolism •Bioactivation • Active Metabolites • Prodrug • Toxification
  • 311. 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
  • 312. 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.
  • 313. 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.
  • 314. 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
  • 315. 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
  • 316. Question •What will happened to drugs that are resistant to drug-metabolizing enzymes?
  • 317. •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
  • 318. Mixed function oxidases or Monooxygenases Capital Letter Arabic Number family Capital Letter subfamily system Arabic Number enzyme
  • 319. 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 ___________
  • 320. 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 ________
  • 321. 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.
  • 322. Reduction Clonazepam • Nitroreductase • Bacterial reductase • Aldo-keto reductase • NADPH cytochrome-c- reductase ENZYMES
  • 323. 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
  • 324. Hydrolysis Procainamide • Esterases • Amidases • Phosphatase • Sulphatases • Expoxide hydroxylase ENZYMES
  • 325. 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.
  • 326. 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
  • 327. 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.
  • 328. 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)
  • 329. 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
  • 330. 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
  • 331. 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.
  • 332. 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).
  • 333. 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.
  • 334. 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)
  • 335. Conjugation with glycine, glutamine, and other Amino Acids •Conjugates carboxylic acids particularly aromatic and arylaklyl acids. •Example: • Benzoic Acid to ________ • Salicylic acid to ________
  • 336. 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
  • 337. 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
  • 338. 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
  • 339. 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
  • 340. 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)
  • 341. 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
  • 342. 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.
  • 343. 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
  • 344. 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
  • 345. 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
  • 346. 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
  • 347. 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.
  • 348. 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.
  • 349. 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.
  • 350. 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.
  • 351. 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.
  • 352. 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
  • 353. 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 ????
  • 354. Genetic/Hereditary Factors •Slow acetylators: Isoniazid SE peripheral neuropathy •Fast acetylators: low therapeutic level and hepatotoxicity
  • 355. 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
  • 356. 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
  • 357. 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
  • 358. 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.
  • 359. 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.
  • 360. 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
  • 361. 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.
  • 362. • Renal excretion: • 3 processes: glomerular filtration  secretion  tubular reabsorption Excretion is Irreversible
  • 363. • 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
  • 364. 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.
  • 365. • 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
  • 366. Kinds of Routes: • Oral Route • Per-oral Route • Rectal Route • Parenteral Route ▫ ID ▫ SC/SQ ▫ IM ▫ IV ▫ Epicutaneous
  • 367. Drug – Receptor Interactions • Lock and Key Concept ▫ Lock  Receptor surface ▫ Key  Drug or Ligand Receptor Drug
  • 368. 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.
  • 369. •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
  • 370. • 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
  • 371. 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.
  • 372. 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.
  • 373. • 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
  • 374. What is QSAR? • Quantitative Structure Activity Relationship -or- • Qualitative Structure Activity Relationship?
  • 375. 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.
  • 376. • 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)
  • 377. 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
  • 378. Steric Features and Pharmacologic Activity •Stereochemistry: Space arrangement of the atoms or three- dimensional structure of the molecule. 378
  • 379. 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. 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. 381 Geometric isomerism (cis- trans isomerism). Steric Features and Pharmacologic Activity
  • 382. 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
  • 383. 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. 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. 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. 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
  • 387. • 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
  • 389. 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
  • 390. 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
  • 391. Selective toxicity oA property of a certain medicinal agent to kill one type of pathogenic microorganisms without harming the host’s cell.
  • 392. 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.
  • 393. 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.
  • 394. 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
  • 396. 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
  • 397. Which among the list is the most water soluble? A. Methanol B. Ethanol C. Propanol D. Butanol E. Pentanol
  • 398. 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
  • 400. 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.
  • 401. 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.
  • 402. 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
  • 404.  Antiseptic  Preservative  Mild counterirritant  Solvent  Astringent  Rubefacient  Mild local anesthetic  Analgesic in neuralgias  Mild sedative  Weak vasodilator  Carminative External use Rubbing alcohol Internal use
  • 405. 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: _____________
  • 406. 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.
  • 407. Glutaraldehyde Disinfectant Solution (Cidex) aka Glutarol, used as sterilizing solution for equipment and instruments that cannot be autoclaved.
  • 408. 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.
  • 409. 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.
  • 410. 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 ________.
  • 411. 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.
  • 412. 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.
  • 413. 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
  • 414. 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.
  • 415. 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
  • 416. 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).
  • 417. Carbamide peroxide Topical Solution (Gly-Oxide): Releases hydrogen peroxide when mixed with water. Uses: Disinfectant antiseptic; effective in treating oral ulcerations
  • 418. 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
  • 419. 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
  • 420. MOA: Protein inactivation by iodination of phenylalanyl and tyrosyl residues; oxidation of –SH groups Lugol’s solution is ____________ Iodine solution is ____________ Iodine tincture is ____________
  • 421. 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.
  • 422. 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.
  • 423. Halazone (p- dichlorosulfamoylbenzoic acid): a white crystalline, photosensitive compound with faint chlorine odor. Use: Sodium salt is water disinfectant (drinking water)
  • 424. 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.
  • 425. 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.
  • 426.  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-)