Refresher Course on Organic Chemistry and Organic Medicinal Chemistry
Mr. Jan Dominique R. Lapig, RPh. April – May 2014
Part I: General Chemistry
The Study of Chemistry
What is Chemistry?
Chemistry is the study of the properties and
behavior of matter.
Science of the composition of matter and changes in composition it may undergo either spontaneously or because of intentionally established environmental condition.
Matter – anything that occupies space and has mass.
Role of Chemistry in Modern Life
• Biological molecules
• Biochemical processes
(cell whole organism)
• Medicines (Inorganic and Organic, Natural and semi-synthetic) eg: Aspirin
• Drug discovery and development (Physicochemical properties, ADME)
Classification of Matter
The basic difference between these states is the distance between the “bodies.”
Gas – bodies are far apart and in rapid
motion.
Liquid – bodies closer together, but still
able to move past each other.
Solid – bodies are closer still and are now
held in place in a definite arrangement.
Classification of Matter
Pure Substances and Mixtures
Mixture – combination of two or more substances in which each substance retains its own chemical identity.
– Homogeneous mixture – composition of this mixture is consistent throughout.
• Solution: example syrup
– Heterogeneous mixture – composition of this mixture varies throughout the mixture.
Classification of Matter
Separation of Mixtures
Mixtures can be separated by physical means.
–Filtration
–Chromatography
–Distillation
Classification of Matter
Separation of Mixtures
Classification of Matter
Pure Substances and Mixtures
It is also possible for a homogeneous substance to be composed of a single substance –
pure substance.
• Element – A substance that can not be
separated into simpler substances by chemical means.
• Atom – the smallest unit of an element that
retains a substances chemical activity.
Classification of Matter
Elements There are ____ elements known. Each element is given a unique chemical
symbol (one or two letters). –C, N, Hg, Au, Mn –Notice that the two letter symbols are
always capital letter then lower case letter because: CO – carbon and oxygen Co – element cobalt
Classification of Matter
Compound: a substance composed of two or
more elements united chemically in definite proportions.
The proportions of elements in compounds are the
same irrespective of how the compound was formed.
Law of Constant Composition (or Law of Definite Proportions): “The composition of a pure compound is always the same, regardless of its source.”
Classification of Matter
Properties of Matter
Physical and Chemical Property
Physical Property – a property that can be
measured without changing the identity of the substance. Example: melting point, boiling point, color,
odor, density
Chemical Property: those that determine
how a substance can be converted to another substance.
Physical and Chemical Property
Intensive properties – independent of sample size. Like temperature, refractive index, density, hardness. Extensive properties – depends on the
quantity of the sample (sample size). Like mass and volume
Properties of Matter
Physical and Chemical Changes
Physical change: the change in the physical properties of a substance.
–Physical appearance changes, but the substances identity does not.
–Water (ice) Water (liquid)
Properties of Matter
Physical and Chemical Changes
Chemical change: (chemical
reaction) – the transformation of a substance into a chemically different substance.
– When pure hydrogen and pure oxygen react completely, they form pure water.
– 2H2 + O2 2H2O
Properties of Matter
Physical and Chemical Changes
Properties of Matter
Physical Properties of Drug Molecule
• Physical States: –Amorphous solid
–Crystalline solid
–Hygroscopic solid
–Liquid
–Gas
Physical Properties of Drug Molecule
• Melting point: temperature at which a solid
becomes a liquid.
• Importance of melting point?
– Water (0°C, 100°C)
– Eutectic mixture
–Packing: property of a solid; is a property
that determines how well the individual molecules in a solid fit together in a crystal lattice
Physical Properties of Drug Molecule
• Boiling point: temperature at
which the vapor pressure of the liquid is equal to the atmospheric pressure
Physical Properties of Drug Molecule
• Polarity: is a physical property of a
compound, which relates other physical properties, e.g. melting and boiling points, solubility and intermolecular interactions between molecules –Bond polarity: is used to describe the
sharing of electrons between atoms.
Physical Properties of Drug Molecule
• Solubility: is the amount of a solute that can be dissolved in a specific solvent under given conditions.
–Solute
–Solvent
–Solvation/hydration
Physical Properties of Drug Molecule
• Unsaturated solution
• Saturated solution
• Supersaturated solution
• Other definition of solubility: the maximum equilibrium amount of solute that can usually dissolve per amount of solvent
Physical Properties of Drug Molecule
• Rate of Solution: is a measure of how
fast a solute dissolves in a solvent. Depends on some properties like particle size, stirring, temperature and concentration
Acid-base properties and pH
Acid-base properties and pH
• Arrhenius acids and bases
–Acid: a substance that produces
hydronium ion
–Base: a substance that produces
hydroxide ion –Neutralization reaction
• Brönsted-Lowry acids and bases
–Acid: proton donor
–Base: proton acceptor
Acid-base properties and pH
• Lewis acid: employ an electron lone
pair from another molecule in completing the stable group of one of its own atoms. aka aprotic acid
• Lewis base: any species that donates a
pair of electrons to a Lewis acid to form a Lewis adduct. For example, OH− and NH3 are Lewis bases, because they can donate a lone pair of electrons.
pH and pKa values
• pH: is defined as the negative of the
logarithm to base 10 of the concentration of the hydrogen ion. The acidity or basicity of a substance is defined most typically by the pH value.
• What is the pH of water? Blood plasma? Stomach?
pH and pKa values
• pH - widely used method of expressing the
hydrogen ion concentration of dilute acids, bases & neutral solutions in terms of pH.
• pH is a mathematical definition of H+ that involves a numerical scale that runs from 0 - 14. It is the negative logarithm of the hydrogen ion.
pH = 1 or pH = - log [H+]
log [H+]
Sample Problem • The H+ concentration of an unknown
liquid is 1 x 10-7 mole/L at 25°C.
• What is the formula to be use?
• Show the complete solution.
• What is the pH of the unknown?
• What is the unknown substance?
pOH
• Although rarely used, the hydrogen ion (OH) concentration can be expressed as pOH, which is the negative logarithm of the hydroxide ion concentration or:
pOH = 1 or pOH = - log [OH-]
log [OH-]
Sample Problem • Compute for the pOH and pH of
the solution if the OH- concentration is 12.1 x 10-10.
• Given: pOH = 9.10, find OH- concentration.
pH and pKa values
• Ka: is a quantitative measure of
the strength of an acid in solution.
• Very strong acids pKa < 1
• Moderately strong acids pKa = 1-5
• Weak acids pKa = 5-15
• Extremely weak acids pKa> 15
Buffer
• Buffers is a solution in which the pH of
the solution is "resistant" to small additions of either a strong acid or strong base. Composed of a weak acid and its conjugate base (e.g. CH3COOH and CH3COO-) or a weak base and its conjugate acid (e.g. NH3 and NH4
+).
• Ex: Blood
• Buffer capacity
Acid-base titration: Neutralization
• Titration: The process of obtaining
quantitative information on a sample using a fast chemical reaction by reacting with a certain volume of reactant whose concentration is known. aka _____________________
• Titrant: the known solution is added from a
buret to a known quantity of the analyte until the reaction is complete
• Endpoint: point at which the reaction is
observed to be completed
Units of Measurement
m/s
seconds
meters
time of units
distance of unitsvelocity of Units
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-F9
5C 32C
5
9F
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
bondside 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=CHCH2CCH
Identify the Hybridization
Identify the Hybridization
Identify the Hybridization
Bond Strength or Bond Energy
Is the energy necessary to break a bond in a diatomic molecule or to dissociate the bonded atoms to their ground state.
Bond Length and Bond Polarity
As the bond polarity increases, the bond length decreases
Hybrid Orbitals and Bond Length
As s character increases, the bond length decreases
Remember the following:
Hybrid Orbital, Bond Length and Bond Polarity
When the s character of the bonding orbitals increases, the bond energy also increases
When the polarity of a bond increases, the bond energy also increases
Bond energy and bond length are inversely related
Remember the following:
Hydrocarbon and
derivatives
Hydrocarbons • Hydrocarbons are
the simplest organic compounds.
• Hydrocarbon derivatives are formed when there is a substitution of a functional group at one or more of these positions.
Hydrocarbon Derivatives
• An almost unlimited number of carbon compounds can be formed by the addition of a functional group to a hydrocarbon.
Type or General Formula
Class Type formula
Alkane CnH2n+2
Alkene CnH2n
Alkyne CnH2n-2
Cycloalkane CnH2n
Cycloalkene CnH2n-2
Cycloalkyne CnH2n-4
Cyclopropane Cyclohexane
Cyclobutane Cyclooctane
Aromatic Ar-H
Alkyl halide R-X
Aryl halide Ar-X
Alcohol R-OH
Primary alcohol R-CH2-OH
Secondary alcohol R2-CH-OH
Tertiary alcohol R3-C-OH
Type or General Formula
Who discovered the structure of benzene?
Friedrich August Kekule
Phenol Ar-OH
Ether R-O-R
Aldehyde R- CHO
Ketone R-CO-R
Type or General Formula
Amine R-NH2
10 amine R-CH2-NH2
20 amine R-CH2-NH-R
30 amine R-CH2-N-R2
40 amine R-CH2-N+-R3
Type or General Formula
Carboxylic acid R-COOH
Acid halide R-CO-X
Acid amide R-CO-NH2
Acid anhydride R-CO-O-CO-R’
Ester R-COOR’
Nitro R-NO2
Type or General Formula
Nitroso R-N = O
Nitrile (cyanide) R-C N
Imine
Imide
Type or General Formula
Diazo
Hydrazino R-NHNH2
Mercaptan (thiol) R-SH
Thioether R-S-R
Enol
Type or General Formula
The chemical CH3CH2COOCH3 is an example of what type of organic compound?
A. Ketone
B. Ester
C. Ether
D. Aldehyde
E. Acid anhydride
PACOP QUESTION
What is the type formula for ethers?
A. RH
B. RX
C. ROR
D. RCHO
E. RCOOR
PACOP QUESTION
The compound with the formula CH3CH2COCH2CH3 is a/an: A. Ketone
B. Aldehyde C. Carboxylic acid D. Ether E. Ester
PACOP QUESTION
The structure shown below is:
C
CC
C
CC
H
H
H
H
HH=
Naphthalene Anthracene Phenanthrene
The structure shown below is:
Isomers • compounds having the same
molecular formula but different structural formulas.
Types of Isomers
• Constitutional or Structural isomers
▫ Isomers with different atom to atom bonding sequencing.
• Stereoisomers
▫ Isomers with the same atom to atom bonding sequence but with the atoms arranged differently in space.
Types of Structural Isomers
• Chain isomers or skeletal isomers
• Positional isomers
• Functional isomers
▫ Tautomers
• Chain/Skeletal isomers ▫ Compounds that differ in the
arrangement of carbons.
Types of Structural Isomers
• Positional isomers ▫ Differ in the position of a non carbon
group.
Types of Structural Isomers
• Functional Isomer ▫ Differ in the functional group.
Types of Structural Isomers
•2-pentanol and 3-pentanol are: A. Functional isomers
B. Positional isomers
C. Chain isomers
D.Optical isomers
E. Stereoisomers
PACOP QUESTION
•2 - pentanol ▫ CH3CHOHCH2CH2CH3
•3 - pentanol ▫ CH3CH2CHOHCH2CH3
Answers:
STEREOISOMERS
• Configurational or Inversional Isomers ▫ Compounds that can be interconverted
by the breaking of chemical bond.
• Conformational Isomers aka rotamers ▫ Interconvert easily at room temperature
through rotation about single bond.
Types of Configurational Isomers
• Enantiomers or enantiomorphs ▫ Stereoisomers that are
non – superimposable mirror images of each other; rotate the plane polarized light in the opposite direction.
• Diastereomers ▫ Stereoisomers that are
non – superimposable and non – mirror images of each other.
Types of Configurational Isomers
Enantiomer vs. Diastereomers
• Geometric isomers (cis, trans)
▫ Cis-trans isomers – differ from each other in the orientation of atoms/groups on a carbon-carbon double bond or in a ring.
Types of Configurational Isomers
trans vs. cis isomers
•Enantiomers differ from one another in:
A.Spatial configuration
B.Rational formula
C.Ion-pair formation
D.Photoelectric effect
PACOP QUESTION
R vs. S Configuration
Cahn-Ingold-Prelog system Determines R or S designation of enantiomers
Chiral or Asymmetric Center
• Chiral or Asymmetric Center ▫ a molecule which contains a carbon to
which four different groups are attached.
Identify which is the Chiral carbon
What type of isomerism is this?
Tautomers • Isomers that differ from each other in
the position of hydrogen atom and double bond.
•Propanone and 1 – propen-1-ol are considered; A. Positional isomers
B. Configurational isomers
C. Tautomers
D.Enantiomers
E. Chain isomers
PACOP QUESTION
Tautomers
• They are diastereomers that differ only in the position of moieties at the first carbon atom.
Anomers
Meso Compound • one whose molecules are superimposable
on their mirror images, even though they contain chiral centers.
Racemic Mixture
• mixture of equimolar concentration of enantiomers in a solution.
IUPAC System Nomenclature
•STEP 1: Name the Parent name.
• Select the longest continuous chain.
Hexane
•STEP 2: Number the Cs in the
chain, from either end, such that the substituent are given the lowest #s possible.
IUPAC System Nomenclature
• STEP 3: Substituent(s)/side chain(s) ▫ Identify the substituent(s) ▫ assigned the # of the C to which it is
attached
3 - methyl
IUPAC System Nomenclature
• STEP 4: Name of the compound • # of the substituent • name of the substituent • parent chain • # is separated from the name with
hyphen • #s are separated from each other by
comma
3 - methylhexane
STEP 5: If substituent occurs more than once in the molecule, the prefixes, di, tri, tetra, etc are used
STEP 6: If a substituent occurs twice on the same carbon, the # of the C is repeated twice
STEP 7: If two or more substituents of different nature are present, they are cited in alphabetical order.
7- ethyl - 4,4’- dimethylundecane
Guide for Organic Nomenclature:
undec-
dodec-
tetradec-
pentadec-
hexadec-
heptadec-
nonadec-
eicos-
tridec-
11
12
13
14
15
16
17
octadec- 18
19
20
Prefix
meth-
eth-prop-
but-
pent-
hex-
oct-non-
dec-
1
2
3
4
5
6
7hept-
8
9
10
Carbons CarbonsPrefix
Trivial Roots of Common Name of Aldehydes and Acids
# of Carbon
Trivial Root
# of Carbon
Trivial Root
1 form – 6 capro –
2 acet – 7 enanth –
3 propion – 8 capryl –
4 butyr – 9 pelargon –
5 valer – 10 capr –
• Give the IUPAC name of the given chemical formula CH3C(CH3)2CH2CH2NH2 A. 1-aminoheptane
B. 1-amino-2,2-dimethylbutane
C. 4-amino-2,2-dimethylbutane
D. 1-amino-3,3-dimethylbutane
E. 7-amino-1-monomethylpentane
PACOP QUESTION
• Give the IUPAC name of the given chemical CH(OH)2CH2CH2CH2CH3 A. pentan-1,1-diol
B. 1-dihydroxypentane
C. 5,5-dihydroxypentanol
D. pentanal
E. 2,2-dipentanol
PACOP QUESTION
• What is the type formula of the chemical methoxyethane? A. RCHO
B. RCOOH
C. RCOOR
D. RCOR
E. ROR
PACOP QUESTION
Name the following:
Mechanism of Reaction: the detailed course of overall reaction. • Sequence of steps
• Details of electron movement
• Bond breaking
• Bond making
• Timing
• A + B [ C ] D + E
▫ A – substrate
▫ B – reagent
▫ C – intermediate
▫ D – main product
▫ E – side product
Mechanism of Reaction: the detailed course of overall reaction.
Types of Bond Cleavage
• Homolytic Cleavage ▫ Characterized by homolytic fission of
bonds and the formation of free radicals.
• Heterocyclic Cleavage ▫ Characterized by heterocyclic fission and
the formation of charged species.
Types of Bond Cleavage
Types of Reagents •1. Nucleophiles (Nu:)
▫ electron-rich species
▫ electron pair donor
▫ attack positions with + charge or low electron density
•2. Electrophiles (E+) ▫ electron-poor species
▫ electron pair acceptor
▫ attack positions with - charge or high electron density
▫ H3O+, BF3, AlCl3, Br2, Cl2, I2
Types of Reagents
Types of Reaction
Intermediates
Types of Organic Reactions
• Substitution reaction
• Addition reaction
• Elimination reaction
• Rearrangement reaction
• Oxidation
• Reduction
Substitution Reaction
Addition Reaction
Elimination Reactions
Rearrangement Reaction
Oxidation
• increase in oxygen
• Increase in electron
• decrease in hydrogen
Reduction
• increase in hydrogen
• decrease in electron
• decrease in oxygen
Atomic Bonds
1. Ionic bonding
2. Covalent bonding
3. Hydrogen bonding or bridging)
4. Van der Waals (London forces)
Ionic Bonding ▫ electrostatic
interaction resulting from the transfer of an electron during the compound formation.
Atomic Bonds
Covalent Bonding ▫ is the attractive force that
exists between two chemicals entities due to their sharing a pair of electrons.
Atomic Bonds
Hydrogen bonding (or bridging) ▫ Attraction between a lone pair of
electrons of a highly electronegative atom and a hydrogen atom bonded to a high electronegative atom.
Atomic Bonds
Vander Waals (London forces)
▫ these are very weak electrical force sometimes referred to as induced dipole – induced dipole interactions.
▫ The associations between aromatic hydrocarbon molecules such as benzene are due to Van der Waals forces
Atomic Bonds
Other electrostatic attraction: a) Ion-dipole Interactions
b) Dipole-dipole interactions
c) Ion-induced dipole interactions
d) Dipole-induced dipole interactions
e) Induce dipole – induced dipole interactions
Atomic Bonds
Alkanes (paraffins, saturated HC)
• Lipid – soluble • Common reactions are:
▫ Halogenation ▫ Combustion
• Upon storage, alkanes are chemically inert with regard to air, light, acids and bases
• In vivo, alkanes are stable • Terminal carbon side – chain
hydroxylation may occur
Alkenes (olefins, unsaturated HC)
• Lipid soluble • Common Reactions are:
▫ Addition of hydrogen or halogen ▫ Hydration to form glycols ▫ Oxidation to form peroxides
• Upon storage, volatile alkenes and peroxides may explode in the presence of oxygen and spark; in vivo, alkenes are relative stable
• Hydration, Epoxidation, Peroxidation and Oxidation may occur
Aromatic Hydrocarbons
• Based on benzene, exhibit multicenter bonding which confers unique chemical properties
• Lipid soluble • Common reactions are electrophillic
substitution such as: ▫ Halogenation, Nitration, Sulfonation, Alkylation
• Upon storage, ArHC are stable • In vivo, ArHC undergo Hydroxylation,
Epoxidation, diol formation
Alkyl Halides • Also known as Halogenated HC
• Lipid soluble
• Common reactions are: ▫ Nucleophillic substitution
▫ Dehydrohalogenation
• Upon storage, alkyl halides are stable
• In vivo, alkyl halides are not readily metabolized
Alcohols • Lipid soluble
▫ LMW Alcohols are water soluble Water solubility decreases as HC chain
length increases
• Common reactions: esterification and oxidation ▫ 1° alcohols – oxidized to aldehydes then to
acid ▫ 2° alcohols – oxidized to ketones
•Upon storage, alcohols are stable
•In vivo, alcohols may undergo ▫ Oxidation
▫ Glucoronidation
▫ Sulfation
Alcohols
Phenols • Lipid soluble
• Fairly soluble in water – ring structure decrease water solubility
• Common reactions: ▫ With strong base to form phenoxide ion
▫ With acids esterification
▫ Oxidation to form quinines, usually colored
• Upon storage, phenols are susceptible to: ▫ Air oxidation ▫ Oxidation on contact with ferric ions
(FeCl3)
• In vivo, phenols undergo: ▫ Sulfation ▫ Glucoronidation ▫ Aromatic hydroxylation ▫ O - methylation
Phenols
Important Alcohols and Phenols
• Methanol
• Ethanol
• Isopropyl alcohol
• Cholesterol
• Glycerol
• Ethylene glycol
• Phenol
• Cresol
• Resorcinol
• Hexylresorcinol
• Menthol
• Geraniol
• Glucose
Ethers • Lipid soluble
▫ LMW ethers are partially water soluble
Water solubility decreases with an increase in HC
• Common reaction is oxidation to form peroxides
• Upon storage, peroxides may explode
• In vivo, ethers undergo O-dealkylation ▫ Stability increases with the size of the alkyl
group
Important Ethers
• Ether: used before as general anesthetic agent ▫ ADR: irritation of mucous
membranes, N & V
• Ethylene oxide: used as gas sterilant for things that cannot be autoclaved
• Eugenol
Aldehydes • Lipid soluble
▫ LMW are water soluble
• Common reactions are: ▫ Oxidation
▫ Hemiacetal and acetal formation
• In vivo, aldehydes may also undergo oxidation to acids or reduction to alcohols
Important Aldehydes
• Formaldehyde
• Acetaldehyde
• Chloral hydrate
• Benzaldehyde
• Cinnamaldehyde
• Vanillin
• Citral
Ketones • Lipid Soluble
▫ LMW are water soluble
• Relatively non – reactive, but may exist in equilibrium with their enol forms
• Upon storage, ketones are very stable
• In vivo reaction includes: Oxidation, Reduction
Amines • Contains an amino group
▫ Amino group can exist in ionized or un-ionized form.
• Lipid soluble ▫ LMW amines are water soluble
Solubility decreases with an increase branching
Quaternary amines, being ionic are water soluble
• Common reactions: ▫ Oxidation
▫ For alkyl amines salt formation with acids
▫ Aromatic amines, which are less basic, have less tendency to react with acids
• Upon storage phenolic amines are susceptible to air oxidation
• In vivo, amines may undergo minor glucoronidation, sulfation, and methylation
Amines
• Primary amines also undergo oxidative deamination
• Primary and secondary amines undergo acetylation
• Secondary and tertiary amines undergo N-dealkylatin
• Tertiary amines, least water soluble undergo N-oxidation
Amines
Carboxylic acids • Lipid soluble
▫ LMW carboxylic acids are water soluble (Na, K salts)
• Common reactions are: ▫ Salt formation with bases
▫ Esterification
▫ Decarboxylation
• On the shelf, carboxylic acids are very stable
• In vivo, carboxylic acids undergo ▫ Conjugation with glucoronic acid,
glycine and glutamine
▫ Beta oxidation
Carboxylic acids
Important Carboxylic acids
• Salicylic acid
• Citric acid
• Lactic acid
• Tartaric acid
• Benzoic acid
• ASA
• PABA
Esters • Lipid soluble
▫ LMW esters are slightly water soluble
• Common reactions of esters is hydrolysis
• Upon storage: ▫ Simple or LMW esters are susceptible to
hydrolysis
▫ Complex or HMW or water – insoluble esters are resistant
• In vivo, esters undergo enzymatic hydrolysis by esterases
Amides • Lipid soluble
▫ LMW are fairly soluble in water
• No common reactions
• Upon storage they are stable
• In vivo, they undergo enzymatic hydrolysis by amidases
Important Amides
•Acetanilide
•Niacinamide or nicotinamide
•Sulfanilamide
Part III: Organic Medicinal Chemistry
Mr. Jan Dominique R. Lapig, RPh
April – May 2014
Medicinal Chemistry
“…let’s make a change on an existing compound or synthesize a new structure and see what happens…”
What is Medicinal Chemistry?
• Medicinal Chemistry is a chemistry-based discipline, involving the aspects of biological, medical and pharmaceutical sciences.
What is Medicinal Chemistry?
• Medicinal Chemistry devoted to the discovery and development of new agents for treating diseases.
- Wilson and Gisvold’s 12th ed.
Synthetic Chemistry
• involves changes designed to transform a starting substance with a particular set of properties.
Definition of Drug
• Is a chemical compound that is used to treat, mitigate, diagnose and prevent diseases both in humans and animals
• Compounds that interact with a biological system to produce a biological response
• Currently, there is no drug that is considered to be totally safe
• Some poison at low doses can be used as drugs; drugs at high concentration can be considered as poison
New Field in Medicinal Chemistry: Biotechnology
• Modified Human Insulin – convenient dosing
• Cell – Stimulating Factors – dosing regimen for chemotherapy
• Humanized Monoclonal Antibodies – target specific tissues
• Fused Receptors – intercept immune cell-generated cytokinases
• Antitoxin – a type of immunobiological
that contains a solution of antibodies derived from the serum of animals immunized with specific antigen.
• Intravenous immunoglobulin (IVIg) – a product derived from blood
plasma of a donor pool similar to the IG pool but prepared so it is suitable for IV use.
New Field in Medicinal Chemistry: Biotechnology
•Toxoid – a modified bacterial toxin
that has been made nontoxic but remains the ability to stimulate the formation of anti-toxin.
New Field in Medicinal Chemistry: Biotechnology
Recall the following principles in understanding medicinal chemistry:
• Physicochemical properties used to develop new pharmacologically active compounds;
• Their mechanism of action; • The drug's metabolism; • Possible biological activities of the metabolites; • Importance of stereochemistry in drug design; • The methods used to determine what “space” a drug occupies.
Physicochemical properties of lead compounds can provide new drugs:
•Cimetidine ▫ as an antinuclear antibody test/drug ▫ Antinuclear antibody (ANA) test
measures the amount and pattern of antibodies in the blood that work against the body (autoimmune reaction).
Answer on Pre-Test • As of the present, it is the most
used and productive method of obtaining new drugs:
A. Random screening
B. Extraction from natural resources
C. Serendipity
D. Molecular manipulation
E. Drug discovery by “luck”
Early Drug Discovery
• Random sampling of higher plants: Opium, belladona, ephedrine
• Accidental discovery: Penicillin
• The use of nutriceuticals or the non-traditional or alternative medicinal agents
Receptors
• substance to which a drug needs to interact with to elicit pharmacologic response
• a relatively small region of a macromolecule which may be an/a: ▫ Enzyme ▫ Structural or functional group/component of
CM, ▫ Specific intracellular substance such as
proteins and nucleic acids
Remember the following terms:
• AFFINITY : ability of a drug to bind with a
receptor.
• INTRINSIC ACTIVITY: ability of a drug to
exert a pharmacologic action.
• AGONIST: drug with affinity and intrinsic
activity.
▫ Description of agonist: mimic the natural ligand for a receptor and may have similar structure to the ligand
• INVERSE AGONIST: these are exogenous
chemical messengers that acts as antagonist, but also eliminate any resting activity associated with a receptor
• ANTAGONIST: drug with affinity but does not have intrinsic activity
▫ Description of antagonist: they bind to regions of the receptor that are not involved in binding the natural ligand.
Remember the following terms:
• AGONIST–ANTAGONIST: in the presence
of antagonist, its effect is agonist, in the absence of an agonist its effect is agonist.
• SENSITIZATION: occur when an antagonists is bound to a receptor for a long period of time. The cell synthesize more receptors to counter the antagonistic effects.
• DESENSITIZATION: this condition may occur when an agonist is bound to its receptor for a long period of time
Remember the following terms:
•TOLERANCE: it is a situation
where increase doses of a drug are required over time to achieve same effect
•DEPENDENCE: it refers to the
body’s ability to adapt to the presence of a drug.
Remember the following terms:
•EFFICACY: it is determined by
measuring the maximum possible effect resulting from receptor-ligand binding.
•POTENCY: relates how effective a
drug is in producing a cellular effect.
Remember the following terms:
Drug Classification
• Pure organic compounds are the chief source of agents for the cure, mitigation or the prevention of disease.
• These remedial agents could be classified according to their origin: ▫ Natural compounds ▫ Synthetic compounds ▫ Semi – synthetic compounds
• Pharmacodynamic agents: Drugs
that act on the various physiological functions of the body (e.g. general anesthetic, hypnotic and sedatives, analgesic etc.).
• Chemotherapeutic agents: Those
drugs which are used to fight pathogens (e.g. sulfonamides, antibiotics, anti – malarial agents, antiviral, anticancer etc.).
Drug Classification
• Drugs can treat different types of diseases:
▫ Infectious diseases: Born (transmitted) from person to person by outside agents, bacteria (pneumonia, salmonella), viruses (common cold, HIV), fungi (thrush, athletes foot), parasites (malaria).
Drug Classification
▫ Non-infectious diseases: disorders of the human body caused by genetic malfunction, environmental factors, stress, old age etc. (e.g. diabetes, heart disease, cancer, hemophilia, asthma, mental illness, stomach ulcers, arthritis).
▫ Non-diseases: alleviation of pain (analgesic), prevention of pregnancy (contraception), anesthesia.
Drug Classification
Drug Development
Life Cycle for new drug :
IND Program • Pharmaceutical company obtains permission
to ship an experimental drug to clinical investigators before a marketing application for the drug has been approved.
• FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk.
• If the application is approved, the candidate drug usually enters a Phase 1 clinical trial.
Pre CLINICAL TRIALS:
• Evaluation of acute and short term toxicity in animals. It Involves : -Lethal dose determination
-Effect of dose at normal level for short/Long term
• Assess how the drug is: absorbed/distributed/metabolized and excreted in animals.
Phase 0 CLINICAL TRIALS
• Parameters measure: PD and PK testing especially oral bioavailability and half life (T½)
• Dose of investigational drug is very small, usually sub-therapeutic dose, involving 10 human subjects
• Often skipped for phase I
Phase 1 CLINICAL TRIALS
• Begins after 30 days of filing IND.
• Drug given to 20-100 healthy volunteers ▫ Duration could vary from 1 month to 1 year.
• Following is studied here : ▫ Drug absorption/Metabolism in human.
▫ Effect on organs and tissues. -Side affect of different dosages.
▫ Thus early evidences on effectiveness are achieved.
Phase 2 CLINICAL TRIALS
• Drug given to 100 - 500 patient volunteers
• Duration could vary from 1 year to 2 years ▫ Following are measured/ studied here: Safety Drug effectiveness in treating the disease Short term side effects in patients Dose range Less than 1/3 of INDs survive phase 2
Phase 3 CLINICAL TRIALS
• FDA consulted before beginning phase 3 ▫ Drug given to 1000-5000 patient
volunteers ▫ Duration could vary from 3 years to 4 years.
• Following are measured/studied here : ▫ Safety of Drug [ Benefits vs. risk analysis ] ▫ Effectiveness possible long term side effects
in patients ▫ Dosing and labeling information
NDA • Formal proposal for the FDA to
approve a new drug for sale in the U.S.
• Sufficient evidences provided to FDA to establish: ▫ Drug is safe and effective.
▫ Benefits outweigh the risks.
▫ Proposed labeling is appropriate.
Historical Timeline: Elixir
1906
1937
No Regulatory control for Drug
safety
Sulfanilamide disaster
Federal Food and Drug Act passed
1938
1961
Thalidomide crisis
Phase 4 : Post Marketing Surveillance • Launched to the Market
• Additional post marketing testing of patients to ▫ Support the use of the approved
indication
▫ Finding new therapeutic opportunities
▫ Extending use of the drug to different classes of patients like children.
Discovery & Development of Organic Medicinal Chemicals:
•Random screening – (with
enzyme linked assays or receptors from gene cloning) of existing drugs lead to identification of new LEAD drug.
▫ e.g. Amantadine
• Rational Drug Design- opposite approach to high-volume screening using techniques like: ▫ X-ray crystallography ▫ Nuclear magnetic resonance
• Leads to the development of drugs; ▫ HIV protease inhibitor ▫ ACE inhibitors ▫ H2 antagonists
Discovery & Development of Organic Medicinal Chemicals:
Helpful mnemonics
•Biotechnology techniques a. Recombinant DNA
b. Mutagenesis- site directed that fuse cell lines
Discovery & Development of Organic Medicinal Chemicals:
Sources of Drugs • PLANT SOURCES -Random sampling of
higher plants led to the discovery of crude plant drugs.
• e.g. opium, belladona, ephedrine
ephedrine Atropa 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
Effects Gastrointestinal Tract
Tissue Depots
a
SYSTEMIC CIRCULATION Serum Albumin Drug
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
OMAsMore hydrophilic
OMAs
CHO2N
OH
CH
CH2OH
NH C
O
CHCl2
Lipophilic
Lipophilic
Hydrophilic
HydrophilicHydrophilic
Chloramphenicol
Solubility Prediction
Soluble Insoluble
Solubility Prediction
Compounds with log Pcalc values greater than +0.5 are considered water insoluble (lipophilic) and those with log Pcalc values less than +0.5 are considered water soluble (hydrophilic).
Acidity and Basicity
• Ionization of acids and bases plays a role with substance that dissociate into ions.
• The ionization constant (Ka) indicates the relative strength of the acid or base.
Consider the following regarding the pH of the medium and the acid/base property of a drug:
• pKa is a property of the drug molecule in a solution while in pH is the property of the medium
• Acidic drug will most likely be dissociated in a basic medium and vice versa
• The sum of the negative logarithm of the dissociation constants of the acid and its conjugate base is always equal to 14
Consider the following:
•Indomethacin pKa = 4.5 well absorbed in ____________.
•Ephedrine pKa = 9.6 well absorbed in _____________.
Forces of Attraction
• Van der Waals
• Dipole-dipole bonding
• Ionic bonding
• Ion-dipole binding
• Covalent bond
• Reinforce ionic
• Hydrogen bond
• Hydrophobic bond
Physicochemical Properties • Polarity
• Acidity/Basicity
• Dissolution
• Particle size and Surface Area
• Salt formation
• Polymorphism
• Chirality
• Hydrates
• Complex formation
• Viscosity
In general, for a drug to exert its biologic effect:
• It must be transported by the body fluid;
• Traverse the required biologic membrane barriers;
• Escape widespread distribution to unwanted areas, endure metabolic attack;
• Penetrate in adequate concentration to the sites of action;
• Interact in a specific fashion, causing an alteration of cellular function.
Drug Absorption and Distribution
• Absorption
▫ transfer of a drug from the site of administration into the systemic circulation or bloodstream
• Oral Administration ▫ The drug must go into solution to pass
through the gastrointestinal mucosa
Factors affecting ABSORPTION
• Chemical nature of drug: ______ and ______ • Particle size: _______ • Nature (Crystalline vs. Amorphous)
▫ like in insulin: semi-lente has shortest activity (100% amorphous) while ultra lente has longest activity.
• Tablet coating • Blood flow: ____ site of most drug absorption.
ROH and ASA is best absorbed in ______ • Surface area • Contact time at the absorption surface
Drug Distribution
• Parenteral Administration ▫ given to patient who cannot take or
incapable of taking oral dosage forms ▫ bypass first pass metabolism ▫ Examples: IV IM/SQ Instraspinal Intracerebral
Blood-Brain Barrier
• composed of membranes of tightly joined epithelial cells lining the cerebral capillaries.
• the brain is not exposed to the same variety of compounds that other organs are.
• e.g. local anesthetics (spinal block)
Factor affecting DISTRIBUTION
• Protein Binding
Drug + Albumin Drug-Albumin Complex
• Major protein: ______ and α-acid glycoprotein
• BOUND vs. UNBOUND
• Example is Warfarin and Phenylbutazone: predict the drug-drug interaction
Protein Binding
• Protein binding may also limit access to certain body compartments. e.g. placenta
• Protein binding also can prolong the drug’s duration of action. How?
• Protein binding limits the amount of drug available for biotransformation and for interaction with specific receptor sites.
• e.g. suramin sodium
Tissue Depot
• The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots.
• Barbiturates activity
Importance of Drug Metabolism
•The basic premise:
• Lipophillic Drugs Hydrophillic Metabolites
(Not Excreted) (Excreted)
• Generally pharmacologically inactive and
• Non-toxic metabolites
METABOLISM • Chemical reaction that occur in the body to maintain life.
• Allow organisms to grow and reproduce, maintain their structures, and respond to their environments.
• Divided into two categories:
• _________ breaks down organic matter
• _________ uses energy to build up or construct components of cells such as proteins and nucleic acids.
METABOLISM • to supply energy for body functions and
maintenance • plays a central role in the elimination of the drugs
and xenobiotics • Goal is to convert drug into _________,
________, and _______ form that are readily excreted.
• It is detoxification process. • ________ is the main site. • converts inactive drug to active form (prodrug
approach) in a process called ____________.
Importance of Drug Metabolism
•Xenobiotic metabolism: it is
used to describe the protective biochemical process by which a living organism either enzymatically or non-enzymatically alters a xenobiotic to a metabolite that is inactive or quickly eliminated from the organism.
Importance of Drug Metabolism
•Termination of Drug Action
•Bioinactivation
•Detoxification
•Elimination
Importance of Drug Metabolism
•Bioinactivation
Importance of Drug Metabolism
•Detoxification
Importance of Drug Metabolism
•Elimination
Importance of Drug Metabolism
•Bioactivation
•Active Metabolites
•Prodrug
•Toxification
Importance of Drug Metabolism
•Active Metabolites
Importance of Drug Metabolism
•Prodrug
Sites of Drug Biotransformation
2. Liver (hepatic metabolism or First Pass Effect
The most important organ in drug metabolism
1. Gastrointestinal Tract Absorb orally administered drugs
Some drugs may decrease Oral bioavailability
Lidocaine (ineffective) Isoproterenol
Meperidine Morphine
Nitroglycerin Pentazocaine
Propoxyphene Propranolol Salicylamide
3. Blood Circulation Absorb orally administered drugs
First-Pass Metabolism • Pre-systemic metabolism
• It is a phenomenon of drug metabolism whereby the concentration of a drug is greatly affected or reduced before it reach systemic circulation
• Limits oral availability of highly metabolized drugs.
General Pathways of Drug Metabolism •Phase I or Functionalization
•provide functional groups (–OH, –COOH, –SH, –NH2) capable of undergoing Phase 2 reactions.
•The enzymes are found in sub-cellular components including cytoplasm, mitochondria and endoplasmic reticulum.
General Pathways of Drug Metabolism
•Usually results in loss of pharmacological activity •Sometimes may be equally or more active than parent. •Reactions includes: * Oxidative Reaction – Gain of Oxygen;
Loss of hydrogen (functional group introduction) * Reductive Reaction * Hydrolytic Reaction
General Pathways of Drug Metabolism
•Phase II or Conjugation Reaction – (Condensation reaction)
•Goal: to attach small, polar, ionizable endogenous compounds to the “handles” of phase I metabolites resulting to the conjugated metabolites which is readily excreted in the urine and feces
Question
•What will happened to drugs that are resistant to drug-metabolizing enzymes?
•Major enzyme system in the liver that is responsible for most of drug metabolism:
A. Monoamine oxidase B. Cytochrome P450 C. Catalase D. Ligase E. Esterase
Question
Mixed function oxidases or Monooxygenases
Capital Letter
Arabic Number family Capital Letter subfamily
system
Arabic Number enzyme
Oxidation •Requires NADP+, O2, microsomal fraction, and NADPH •Active toward broad spectrum of compounds • Incorporates only one O atom into the substrate • Involves a heme protein, which absorbs visible light of 450nm after reduction and exposure to CO •Name ___________
Oxidation •Oxidation is the addition of oxygen and/or the removal of hydrogen.
•Hydroxylation is the introduction of an OH group by oxidation.
•Example: aniline into ________
Reduction •Loss of oxygen ; Gain of Hydrogen •Chemical reaction in which the substrate gains electrons. •Reductions are most likely to occur with xenobiotics in which oxygen content is low. • Important in the metabolism of carbonyl to alcohol derivatives, nitro and azo group to amino acid derivatives.
Reduction
Clonazepam
• Nitroreductase • Bacterial reductase • Aldo-keto reductase • NADPH
cytochrome-c-reductase
ENZYMES
Hydrolysis •Common for drug with functional groups like esters and amides
•Addition of water with breakdown of molecule
•Functional group unmasking
N
H
O
NNH2N
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
HH
OAc
(CH3)3 N+
HH
OAcH
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-)
Has bactericidal action against a broad spectrum of G+ and G- bacteria, fungi and protozoa.
MOA: lower down the interfacial tension: HOW??? dissolution into the microbial CM
destabilization/interference of the enzyme system cell lysis
Please refer to page 187 for the advantages and disadvantages of cationic surfactants.
Benzalkonium Chloride (Alkylbenzyldimethylammonium chloride, Zephiran®)
Uses: Detergent, emulsifier, wetting agent Antiseptic for skin and mucous
membrane Irrigation solution Storage of surgical instruments
Methylbenzethonium Chloride (Diaparene®): used to control diaper rash caused by bacterium ammoniagenes which liberates ammonia in decomposed urine. A general antiseptic
Benzethonium Chloride (Phemerol chloride); is a colorless crystalline powder that is soluble in water, alcohol, and most organic solvents.
Uses: Similar to Benzalkonium chloride
Cetylpyridinium Chloride (1-hexadecylpyridinium chloride, Ceepryn®)
Uses: General antiseptic for skin, laceration, irrigation and available as throat lozenges and MW
Chlorhexidine Gluconate (Hibiclens®); most effective of a series of antibacterial biguanides, broad spectrum antibacterial activity (inactive against acid fast bacterial, spores and viruses).
Uses: Antiseptic topically
Cationic dyes are active against gram + microorganisms and inactivating fungi; G- are resistant
Forms colorless leucobase under alkaline condition
Useful dyes (present)
Gentian violet
Basic fuchscin
Methylene blue
Triphenylmethane dye
Thiazine dye
Gentian Violet (hexamethyl-p-rosaniline
chloride, Genepax®): aka crystal violet, methyl violet, methylrosaniline chloride
Available as green powder or green flakes with metallic sheen
Uses:
Available as vaginal suppository or _______ for the treatment for yeast infections.
1-3% solution for the treatment of ringworm and yeast infection.
Orally as an anthelmintic for threadworm and pinworm.
Basic fuchsin: mixture of
chlorides of rosaniline and p-rosaniline; a green crystalline powder with a mettallic apperance
Component of Carbol-fuchsin solution (Castellani’s paint), treatment of fungal infections like ringworm and athlete’s foot.
Methylene blue (Urised®): dark green
powder with a metallic appearance; can cause methemoglobinemia; can tint the urine and stool ________
Uses:
Has weak antiseptic properties (useful for the treatment of cystitis and urethritis)
antidote for cyanide and nitrate poisoning
Elemental Mercury: local anti-infective
and treatment of syphilis Two Classes of Organomercurials Compounds with at least one carbon-mercury
bond that does not ionize readily Compounds with mercury bonded to
heteroatoms SAR: organic moieties increase lipid solubility,
render the compound bacteriostatic MOA: reacts with the –SH of enzymes and other
proteins by forming R-S-Hg-R’
Nitromersol (Methaphen®)
MOA: formation of covalent compounds Use: antiseptic for skin and eye infection
Thimerosal: previous active
composition of merthiolate or “gamot na pula” is a cream colored, water-soluble powder, non-staining and non-irritating to tissues. Weakly bacteriostatic agent
Merbromin: mercurochrom, red-
orange
Prevents contamination
Ideal characteristics of preservatives:
Effective at low concentration against all possible microorganims
Non toxic
Compatible with other ingredients
Stable for the shelf life of the products
Esters of p-hydroxybenzoic acid
“PARABENS”: useful antifungal preservative
for liquid dosage forms; has low toxicity
SAR: increase activity as MW increases
Methylparaben (methyl-p-hydroxybenzoate): white crystalline powders; MOLDS
PropYlparaben (propyl-p-hydroxybenzoate): white crystalline powders; YEAST
Butylparaben (n-buty-p-hydroxybenzoate)
Ethylparaben (ethyl-p-hydroxybenzoate)
Chlorobutanol (1,1,1-trichloro-2-
methyl-2-propanol, Chloretone®) at 0.1-0.5% is bacteriostatic agent in pharmaceuticals for injections, ophthalmic use and intranasal administration
Benzylalcohol (Phenylcarbinol,
Phenylmethanol): is a clear liquid with an aromatic odor;
Uses: commonly used for vials for injectable drugs in 1-4% water or saline solution, local anesthetic effect, antiseptic in the treatment of pruritic skin condition.
Phenylethyl alcohol (Orange oil,
Rose oil). Benzoic acid and its esters are naturally occurring in gum benzoin and in Peru and Tolu balsams
Uses: Antiseptic in lotions, ointments and MW; Preservative in foods and pharmaceuticals at low pH
Sodium benzoate Sodium propionate
Sorbic acid (2,4-hexadienoic acid):
effective antifungal preservatives esp. in preparations containing sugar
Potassium sorbate Phenylmercuric nitrate: preservative
in injectable drugs, bacteriostatic efficacy is reduced in the presence of serum
Phenylmercuric acetate
(acetoxyphenylmercury) occurs as white prisms.
Answer on Pre-Test
• Which of the following agents is not used for local candidiasis? A. Nystatin B. Gentian Violet C. Griseofulvin D.Miconazole E. Clotrimazole
Fungal infections are caused by microscopic organisms that can invade epithelial tissue caused by yeast, molds etc.
Fungal infections classification: oSuperficial infections (Cutaneous):
caused by dermatophytes → incidence rate is high.
oDeep-seated mycoses: transmitted from one host to another.
Systemic infections are caused
by the inhalation of spores affecting deeper tissues and organs and cause fungal pneumonia.
This pneumonia cannot be transmitted from human to human.
Opportunistic Fungal infection: can cause life
threatening infection to immunocompromised patients like patient with leukemia, cancer, HIV, diabetes and patients currently using immunosuppressive agents, cytotoxins, irradiation and even steroids.
Subcutaneous mycoses: refers to a
group of fungal disease which both the skin and subcutaneous tissues are involved (internal organs are not affected)
Characteristics: soil saprophytes of very low grade virulence and invasive ability and they gain access as a result of trauma to the tissue.
Skin: formidable barrier to drug
penetration
Fatty acid and Derivatives: all fatty
acid and fatty acid derivatives (salts) have antifungal properties due to sebum fraction (part of innate immune system)
SAR: higher molecular weight fatty acid have the advantage of having lower volatility; salt form are fungicidal
Propionic acid: non-irritating and
non-toxic; present in perspiration or sweat; around 0.01% is fungicidal.
Zinc propionate: used as fungicide on
adhesive tapes
Sodium caprylate and Zinc caprylate
Undecylenic acid (10-undecenoic
acid, Desenex, Cruex): obtained from the destructive distillation of castor oil (ricinoleic acid)
Use: treatment of athlete’s foot
Triacetin (Glyceryl triacetate,
Enzactin®, Fungacetin®): is a fungicide, a colorless oily liquid that release acetic acid upon hydrolysis.
Salicylic acid (use: antifungal and
keratolytic) and Resorcinol (m-
hydroxyphenol) (use: antiseptic and keratolytic)
Benzoic acid: only antifungal that
cannot penetrate the skin.
Should be use in combination to provide therapeutic effect.
Phenol and their derivatives: MOA: interfere with cell membrane integrity and
function in susceptible fungi.
Haloprogin (Halotex®): white to pale yellow and photosenstive 1% cream for the treatment of superficial tinea infection.
Clioquinol (Vioform®): spongy, light-sensitive, yellowish white powder; substitute for iodoform
Use: tx of jock itch and athlete’s foot, 3% tx of vaginitis
Ciclopirox olamine (Loprox®): a broad
spectrum antifungal agent used topically.
AOC: cutaneous candidiasis, Tinea corporis, Tinea cruris, Tinea pedis, and Tinea versicolor.
Second line agent for onychomycosis
MOA:
Low concentration: block the transport of amino acids into the cell
High concentration: lost of membrane integrity and cellular constituents
Flucytosine (5-FC, Ancobon®): orally active,
narrow spectrum antifungal agent.
MOA: incorporation of fluorinated pyrimidine to fungal RNA following selective deamination of 5-fluouracil, which is an anti-metabolite that inhibits thymidylate synthethase and thus DNA synthesis refer to figure 6.3
Use: tx of systemic Candida and Cryptococcus spp. infections.
Polyenes: isolated from soil bacterium
Streptomyces and has the structural requirement:
o Large lactone ring (26 C: Natamycin; 38 C: Amphotericin B and Nystatin)
o Series of OH groups on the acid portion of the ring
o Glycosidically linked deoxyaminohexose sugar __________
o Conjugated double bonds (Natamycin is pentaene; Nystatin is hexaene; amphotericin B is heptaene)
Polyenes cont...
o Broad spectrum anti-fungal agents against pathogenic yeast, molds and dermatophytes (with anti-protozoal properties)
o Use of polyenes is limited because: 1) toxicity of drugs 2) low water solubility 3) poor chemical stability
o Topical agents for superficial fungal infections
Binds with sterols in cell membrane as “false membrane” component (-static at LOW concentration); generalized membrane (-cidal at HIGH concentration) and interferes permeability and transport functions.
Can form a pore in the membrane, creating a transmembrane ion-channel resulting in the loss of intracellular potassium ions.
Amphotericin B (Fungizone®): isolated in 1956 by Gold et. al from ______________
Amphoteric substance
Used to treat serious, potentially life threatening infections
Parenteral form (except IM) is an aqueous colloidal dispersion stabilized by sodium deoxycholate (Note: NSS is not use, WHY???)
Selective action on the CM of fungi and some protozoa due to the affinity for _______ than cholesterol
Limitation (Ampothericin B) for use due to:
o Nephrotoxicity (80%)
o Generalized toxic reactions (fever, headache, anorexia, GI distress, malaise)
o Hypokalemia, anemia
o Pain at the injection site and thrombophlebitis
o Hemolysis
o Intrathecal route: neurotoxicity
Nystatin (Mycostatin®) isolated by
Hazen and Brown (1951) from ________
The ring (aglycone) is called as ______
Natamycin (Natacyn®) obtained
from _______
Treatment of conjuctivitis, blepharitis and keratitis
Griseofulvin (Grisovin®) 1st reported by
Oxford et. al and was isolated from ____________
Note to pharmacist in dispensing Griseofulvin (-static)
Adverse effects: rash/urticaria, GI upset, headache, dizzines and insomia
MOA: Mitotic spindle poison (binds with the tubulin dimes required for microtubule assembly)
Result of random screening
MOA: interfere early step of ergosterol biosynthesis: inhibition of squalene epoxidase (increase squalene concentration destabilizes the fungal cell membrane)
epoxidation ring opening (squalene zipper) ergosterol biosynthesis
Activity (1) –static against pathogenic yeast and –cidal against dermatophytes and filamentous fungi
Naftifine HCl (Naftin): 1% cream/gel is
used topically against ringworm, athlete’s foot and jock itch
Terbinafine HCl (Lamisil) use is same
with Naftifine but active against onychomycosis
Terbenafine > Naftifine
Tolnaftate (Tinactin): thioester of β-
naphthol that inhibits squalene epoxidasase (-cidal)
Clotrimazole
Econazole nitrate
Butoconazole nitrate
Sulconazole nitrate
Oxiconazole
Tioconazole
Represents a class of synthetic antifungal agents with a broad spectrum of activity and possess a unique mechanism of action.
Miconazole nitrate
Ketoconzazole
Terconazole
Itraconazole
Fluconazole
Voriconazole: newest among azole
Posaconazole: Phase II
N
X
N (CH2)n C
R1
R2
Ar
The triazole or imidazole ring are essentialfor the activity, the N 3 binds to the ferric iron atom in the hemeprosthetic group to provent the activationof oxygen for insertion into lanosterol.The activity: X=N > X=CH
atom of azole ring
1The substitution must on theN ,other position will lose
the activity
The 2,4 position of aromatic ringare intruduced eletron withdrawinggroup,such as, F,Cl, will increaseantifungal activity.
the varying of R1 and R2 can be :R1= OH, or R, R2 formed a 1,3dioxapetane.
Inhibition of cytochrome P-450 enzyme that catalyzes 14--demethylation of lanosterol to ergosterol, accumulation of 14-methylated sterols cause permeability disturbance.
Clotrimazole (Canesten): broad-
spectrum, used topically for the treatment of tinea and candidiasis and vulvovaginal candidiasis (tablet) SE: severe GI disturbances
MOA: interferes with amino acid transport into the organism by an action of CM
Econazole Nitrate (Spectazole)
Butoconazole Nitrate (Femstat)
Sulconazole Nitrate (Exelderm)
Oxiconazole Nitrate (Oxistat)
Tioconazole (Vagistat): useful for
vulvovaginal candidiasis. More effective against Torulopsis glabrata.
Terconazole (Terazole): exclusively for
the control of vulvovaginal monolialiasis
Miconazole Nitrate (Daktarin):
treatment for systemic fungal infection and chronic mucocutaneous candidiasis. AE: Thrombophlebitis, pruritus, fever, GI upset
Ketoconazole (Nizoral): 1st orally
active broad spectrum (imidazole); useful for systemic infection, HEPATOTOXIC
RPh’s Note: dispensing and DI
Itraconazole (Sporanox): one
Orally active, broad spectrum Acidic environment requires for optimum
absorption Food enhances absorption 99% protein bound, increase plasma
concentration of anti-histamines Important alternative to Ketoconazole
Fluconazole (Diflucan): the only water soluble azole (bis-triazole) with broad spectrum of activity.
Excellent oral bioavailability Plasma protein binding is <10% Recommended for the treatment and
prophylaxis of disseminated and deep organ candidiasis
Agent of choice: cryptococcal meningitis DOC: fungal meningitis
Terconazole (Terazol) AE:
Thrombophlebitis, pruritus, fever, GI upset
Voriconazole
Posoconazole
Inhibitor of D14 reductase and D7 – D8 isomerase
Amorolfine
Echinocanadins: large cyclic peptides
linked to a long fatty acid.
Products: Caspofungin, Micafungin, Anidulafungin.
MOA: inhibits the synthesis of 1,3-β-d-glucan synthase resulting to the disruption of the fungal cell wall and cell death. Non competitive inhibitor
of 1,3-β-d-glucan synthase
A cyclic depsipeptide produced by ______________
MOA: act as a tight binding noncompetitive inhibitor of the enzyme inositol phosphorylceramide synthase.
IPC synthase: essential for fungal
sphingolipid biosynthesis
Obtained by ____________ on the basis of model compounds that is used as antibacterial agent for local, systemic and/or urinary tract infections.
Examples: quinolones, heterocyclic (nitro) compounds and sulfonamides.
Patterned after _________ which is a ___________.
Isosteric heterocylic groupings like:
o Napthyridines: Nalidixic acid, Enoxacin
o Cinnolines: Cinoxacin
o Quinolones/Fluoroquinolones: Norfloxacin, Ciprofloxacin, Ofloxacin, Lomefloxacin, Sparfloxacin
First generation quinolones o Highly protein bound o Mostly used for UTIs
Fluoroquinolones (2nd to 4th generation)
o Modified 1st generation quinolones o Not highly protein bound o Wide distribution to urine and other tissue;
limited CSF penetration o 2nd generation Norfloxacin and Enoxacin also
indicated for STD like uncomplicated gonorrhea and chanroid (enoxacin)
Board Questions
•Mechanism of action of quinolones: A. Injury to plasma membrane
B. Inhibition of DNA gyrase
C. Protein synthesis inhibition
D.Production of toxic free radicals
Largely confined to G-
Urinary pathogens, Escherichia, Klebsiella, Enterobacter, Citrobacter, Proteus
Fluoroquinolones: effective against P. aeruginosa, N. gonorrhea, H. influenzae, G+ cocci, anaerobes
Useful for penicillin resistant gonococci, methicillin resistant Staph. aureus and aminoglycoside resistant P. aeuruginosa.
Drug interaction: o Decrease absorption of Al, Mg and Ca antacids o CYP450 inhibition
Adverse effects: o CNS: headache, irritability, tremors, sleep
disorders, vertigo, anxiety, agitation, deleurium, hallucinations, seizure (rare)
o GI: N & V o Allergic skin reaction: rashes, urticaria, pruritus o CV: torsades de pointes (rare) o Muskoskeletal: rupture tendon o Neurologic: polyneuropathy
Drug Names Spectrum
1st Nalidixic acid (NeGram) Cinoxacin
Gram– but bot Pseudomonas species
2nd Norfloxacin Ciprofloxacin
Enoxacin Ofloxacin
Gram– (including Pseudomonas spp., some Gram+ (S. aureus) and some atypical microorganisms
3rd Levofloxacin Sparfloxacin Moxifloxacin Gemifloxacin
Same as 2nd generation with extended G+ and atypical coverage
4th Trovafloxacin Same as 3rd generation with broad anaerobic coverage
Widely distributed in the body (CSF) Food delays absorption Binds divalent cation (decrease
absorption) Increase effect of warfarin AOC for gastroenteritis caused by G-
bacilli Used for acute and chronic UTI, VD and
chronic infections involving renal tissues
Resembles ciprofloxacin in antibacterial spectrum and potency; increased concentration in CSF
Superior oral absorption and bioavailability
Food delays absorption Uses: LRTI: bronchitis and pneumonia,
PID, acute gonococcal urethritis with Doxycycline, UTI, Prostatitis, Infection of the skin and soft tissues
•More potent optical isomer of ofloxacin: A. Opto
B. Cis
C. Levo
D.Trans
E. Dextro
Board Questions
Spectrum: G-, G+ (S. aureus including MRSA and S. pneumoniae) Legionella pneumophila, atypical respiratory pathogens, M. tuberculosis
Indications: Chronic bronchitis and CAP, Nosocomial pneumonia, SSTIs, intra-abdominal infections
ADR: Blood glucose disturbances in DM patients, QTC prolongation, torsades de pointes, arrhythmias, N & V and GI Upset
Safety and efficacy not established in patients < 18 y/o
Spectrum: G- (S. aureus including MRSA and S. pneumoniae), atypical respiratory pathogens (Legionella pneumophila, C. pneumoniae and M. pneumoniae) M. tuberculosis, G- anaerobes
Indications: Chronic bronchitis and CAP, Bacterial conjunctivitis, sinusitis
ADR: blood glucose disturbances in DM patients, QTC prolongation, torsades de pointes, arryhtmias, N & V and GI upset
Only quinolone that is taken OD
Most phototoxic: WHY???
Primarily used for acute bacterial exacerbations of chronic bronchitis and prophylaxis of infections following transurethral surgery
For acute cystitis and chronic UTI
Higher potency against G+ bacteria
Skin and soft tissue infection in LRTI and PID
Bacterial gastroenteritis and cholecystitis
UTI
Gonorrhea: β-lactam resistant strains
Diarrhea: caused by Shigella, toxigenic E. coli, Salmonella, thypoid
Respiratory infection: Bacterial (Haemophilus, Strep spp., Pseudomonas) and non bacterial like Chlamydia, Mycoplasma and Legionella
Osteomyelitis
First nitroheterocyclic compound to be introduced into chemotherapy.
Derivatives of 5-nitro-2-furaldehyde, formed on reaction with the appropriate hydrazine or amine derivative.
Antiprotozoal (Nifurtimox) in the tx of trypanosomiasis and leishmaniasis
Ameobacide (Metronidazole)
AE: mutagenic and carcinogenic
SAR: Anti-microbial property is present only when the nitro group is in the 5-position.
MOA: reduction (nitrofuran reductase) of the nitro group coupled with the formation of free radicals (reactive intermediates) which cause damage to ribosomal proteins especially DNA, causing inhibition of DNA, RNA, protein, and cell wall synthesis.
Nitrofurazone: topically in the treatment of burns and prevent bacterial infection associated with skin grafts
Furazolidone: recommended for the oral treatment of bacterial or protozoal diarrhea
Nitrofurantoin: suitable for oral use in the treatment of UTI. Microcrystalline form improve GI tolerance without interfering oral absorption
Board Questions •Methenamine is decomposed into ____ at a urine pH of 5.5. This is responsible for methenamine’s urinary tract antiseptic property:
A. Formaldehyde B. Acetone C. Carboxylic acid D. Ethanol
Methenamine: prepared by evaporating a solution of formaldehyde and strong ammonia water to dryness.
MOA: antibacterial activity depends on liberation of formaldehyde and enhanced by acidifying with sodium biphosphate or ammonium chloride
Tx for chronic UTI
Ineffective for urease containing microorganism – WHY???
Salt form like Methenamine mandelate (Mandelamine) and Methenamine hippurate (Hiprex) are used as urinary antiseptic.
Alleviate pain and discomfort caused by UTI
Soluble and concentrates in urine
Phenazopyridine HCl (Pyridium)
Formerly used as urinary antiseptic Local analgesic effect on the mucosa of the
UT; Used in combination (Azo-gantrisin and Urobiotic)
May tint the urine _______________ The stain is removed by sodium dithionite
Causative organism — Mycobacterium tuberculosis; live inside the macrophages and lysosomes; it is a gram positive acid fast bacillus.
Usual locations of Tuberculosis —Lungs (PTB), Bones, Intestine, Kidney, Intestine, Lymph Nodes, Breast and Tubercular Meningitis.
Management: “shotgun therapy”
Aim of therapy — treatment must be for longer period because response to chemotherapy is slow, because of: o Slow rate of growth o Intracellular location o Large number of actively multiplying
bacteria must be killed. (best drug is Isoniazid)
• Combination therapy in the treatment of tuberculosis contain the following drugs, except: A. Ethambutol B. Rifampicin C. Isoniazid D. Streptomycin E. A, B and C
Board Questions
Why combination therapy is given in TB? o To broaden the spectrum o To reduce the toxicity of individual drugs o To prevent the emergence of resistance
2 types o 1st line drugs (RIPES) o 2nd line drugs (Aminoglycosides, p-
aminosalicylic acid (PAS), capreomycin, ciprofloxacin, clofazimine, cycloserine, ethionamide, levofoxacin, rifabutin)
Current recommended treatment for pulmonary TB has three regimens:
6 Month Regimen—virtually 100% effective, more expensive. (usually only used in pulmonary TB)
First 2 months— RIPE; Next 4 months— RIP
Prophylactic Dose:
Isoniazid: dose is 300mg/day (5mg/kg/day) or 900mg twice weekly for 6 to 12 months in case of immunocompromised patients.
Rifampicin: prophylaxis for the patients
who are unable to take isoniazid; have close contact with a case of active TB caused by an isoniazid resistant Rifampicin-susceptible strain.
Isoniazid: safest, most potent and
effective against all forms of M. tuberculosis; Bactericidal.
Readily absorbed from the GIT Toxic effects: I-N-H Metabolism and excretion: __________ Slow acetylators: Egyptians Rapid acetylators: Eskimos, Asian Filipinos are slow acetylators, Lin et. al.,
1994
Ethionamide: secondary drug
for the treatment of TB
Used in the txt of INH resistant TB
AE: GI intolerance, visual disturbances, hepatotoxicity.
Pyrazinamide: first line agent in short term TB
Effective in low pH environment Penetrates inflamed meninges Synthetic analogue of Nicotinamide Can kill TB bacilli in acidic pH up to 5.5
(intracellular, within the macrophage and lysosome)
Cannot kill TB bacilli in the blood because of high pH
Mechanism of Action:
Drug is converted into Pyrazinoic acid by Pyrazinamidase in M. tuberculosis and kills the bacteria, the target and the mechanism of action is unknown.
SE: interfere uric acid secretion
Ethambutol: active against dividing
mycobacteria
Stereospecific; in combination with other antitubercular drug specially in PTB
Mechanism of Action:
Inhibits the synthesis of Arabino-galactan which is an essential component of the mycobacterial cell wall.
Inhibition of the incorporation of mycolic acid into the cell wall of the microorganisms
Adverse effects: Retinobulbar optic neuritis (most
common)—loss of visual acuity, red-green color blindness and blindness.
Should not be given to children Hyperuricemia—may occur Hypersensitivity—very rare
Aminosalicylic acid and aminosalicylate
sodium second agent for TB MOA: prevents incorporation of PABA in
dehydrofolic acid molecule
Clofazimine: basic red dye that exerts a slow
bactericidal effects on M. leprae Anti-inflammatory and immune-modulating
effects Tx of skin lesions caused by M. ulcerans AE: sever GI intolerance, skin pigmentation,
ichtyosis, dryness, rash, pruritus.
Rifampin (Rifampicin) It is a complex semisynthetic derivative of
Rifamycin produced by _____________ Most active first line agent against TB When taken with paracetamol, APAP is
inactivated Can tint the urine, stool, saliva, tears, skin
_____________ AE: ______(common) and allergic reactions
MOA: Rifampicin inhibits DNA dependent RNA polymerase which is responsible for RNA synthesis
Drugs that can affect urine color • Red or pink urine: Rifampicin
(common), phenazopyridine
• Orange urine: Rifampicin, sulfasalazine
• Blue or green urine: Amitriptyline, indomethacin, propofol
• Dark brown/tea-colored urine: Chloroquine, primaquine, metronidazole, nitrofurantoin
Rifabutin: prophylaxis of disseminated
MAC in AIDS patients
Cycloserine: isolated from Strep.
orchidaceus, Strep. garyphalus, Strep. lavendulus
MOA: prevents the synthesis of cross linking peptide in the formation of bacterial cell walls
Recommended for patients who failed to respond to other anti-TB drugs or resistant TB
Sterile capreomycin sulfate:
aminoglycoside, strongly basic cyclic peptide isolated from Strep. capreolus
Second line agent, alternative to streptomycin
Isoniazid Peripheral Neuropathy
Rifampicin Cholestatic jaundice + renal toxicity + Flu like syndrome
Pyrazinamide Hepatotoxicity + Hypeuricemia
Ethambutol Retinobulbar optic neuritis
Metronidazole
Spectrum of activity: anaerobic, microaerophillic bacteria and protozoa
“triad of features” which includes antiamebic, antigiardiasis, and anti-trichomonal.
Mechanism of action: enters
bacteria via cell diffusion
Activated via single reduction step by bacteria forms radicals reacts with nucleic acid(by covalently binding the 5-nitro group to DNA) cell death
Diloxanide: esters are to be activated to exert amebicidal activity. Tx of asymptomatic carriers of E. histolytica
8-hydroxyquinoline: antibacterial and antifungal, parent compound
Iodoquinol: tx of acute and chronic intestinal amoebiasis AE: neuropathy
Emetine and dehydroemetine: alkaloids obtained from Ipecac
oAmoebicidal
oProtoplasmic poison
oTx fo liver disease since alkaloids concentrates mainly at the liver
oTx of balantidial dysentery and fluke infestations
Pentamidine isethionate: oTx of pneumonia cause by P. carinii oTx for the prophylaxis of African
trypanosomiasis oTx for visceral leishmaniaisis
Atovaquone: highly resistant to
malaria, highly lipophillic, water insoluble analogue of ubiquinone 6 o Alternative tx of PCP caused by P. carinii o Originally an antimalarial Plasmodium
falciparum develops tolerance to its action
o High fat diet to improve absorption
Eflornithine: inhibitor of ornithine
decarboxylase
o Tx of West African sleeping sickness caused by T. gambiense
Nifurtimox: nitrofuran derivative
o Tx for acute and DOC for chronic Chaga’s disease
Benznidazole: nitroimidazole
derivative as an alternative in the treatment of Chaga’s disease o SE: peripheral neuropathy, bone
marrow supression
Melarsoprol: DOC for later stages
of African trypanosomiasis o Excellent penetration into the CNS o Causes arsenic toxicity
Sodium stibogluconate:
pentavalent antimony-compound intended primarily for the tx of various leishmaniasis (DOC)
Dimercaprol: heavy metal poison
MOA: chelation
Suramin sodium: DOC for long
term prophylatic agent for African trypanosomiasis
Drugs that have the capability of ridding the body of parasitic worms or helminths
oPlatyhelminthes: tapeworms and flukes
oNemathelminthes: nematodes or true round worms
Ascaris lumbricoides (round worm) - “PAM” Pyrantel palmoate, Albendazole, Mebendazole
Hookworm -“PAM” Pyrantel palmoate, Albendazole, Mebendazole o Ancylostoma duodenale (old-world
hookworm) o Necator americanus (new-world hookworm)
Trichuris (Trichuris trichuria)- “AM” Albendazole, Mebendazole
Strongyloides - Ivermectin Enterobius vermivularis - “PM”
Pyrantel palmoate, Mebendazole Trichinella - Mebendazole Cutaneous larva migrans - “AI”
Albendazole, Ivermectin Onchocerca volvulus - Ivermectin
Schistosoma haematobium - Praziquantel
Schistosoma mansoni - Praziquantel
Schistosoma japonicum - Praziquantel
Paragonimus westermani - Praziquantel
Fasciola hepatica - Bithionol or Triclalbendazole
Fasciolopsis buski - Praziquantel or Niclosamide
Taenia saginata - Praziquantel or Niclosamide
Taenia solium - Praziquantel or Niclosamide
Hymenolepsis nana - Niclosamide
Cysticercosis - Albendazole
Diphylobothrium latum - Praziquantel or Niclosamide
Echinococcus granulosus: Albendazole
Piperazine: MOA: increase the resting
potential of the helminth muscle so that the muscle membrane is supressed leading to flaccid paralysis
Diethylcarbamazepine citrate:
selective anthelmintic activity against filariasis and ascariasis
Pyrantel pamoate: a
depolarizing neuromuscular blocking agent
Antagonize piperazine ADR: GI effect MOA: promotes depolarization of the
helminth’s myoneural junction and cholinesterase inhibition spastic paralysis and loss of muscle activity
Thiabendazole Mebendazole: broad spectrum
anthelmintic activity similar with thiabendazole
MOA: inhibition of glucose uptake leading to depleted glycogen storage decrease ATP synthesis
AE: abdominal discomfort and teratogenic
Albendazole: broad spectrum
anthelmintic activity against nematodes (intestinal)
Single-dose tx for ascariasis, hookworm, and trichuriasis
Multiple dose therapy with albendazole for the tx of pinworm, threadworm, capillariasis, chlornorchiasis and hydatid disease.
Answer on Pre-Test • All of the following are effective and
clinically useful against worm infestation caused by Ascaris lumbricoides, except:
A. Niridazole B. Mebendazole C. Piperazine D. Pyrantel pamoate E. Thiabendazole
Niridazole: Active against blood
trematodes: Schistosoma hematobium, S. japonicum and S. mansoni.
MOA: inhibits the conversion of the active form of schistosomal glycogen phosphorylase into inactive form
Niclosamide: taenicide, a saline purge 1-
2 hrs after ingestion of niclosamide is recommended to remove the scolex and worm segments
Potent taenicide that segments worms and scolex
MOA: inhibition of glucose uptake, inhibition of energy production by anaerobic metabolism and inhibition of inorganic phosphate incorporation into ATP
Bithionol: chlorinated bisphenol,
fasciolicide and taenicide
Oxamniquine: antischistosomial (S.
mansoni) agent for intestinal schistosomiasis. Activated mainly by esterification and alkylates the DNA of helminth inhibition of nucleic acid metabolism
Praziquantel: an isoquinoline
derivative (levo form most active) broad spectrum against flukes
DOC: blood flukes
MOA: produces tetanic-like contraction within the muscle system of the fluke (alteration in the influx of calcium ions) leading to segment worms
Ivermectin: a 16 membered macrocyclic
lactone obtained from Strep. avermitilis
MOA: act as GABA agonist or as an inducer of chloride ion inlfux leading to hyperpolarization and muscle paralysis.
Used in controlling endo and ecto parasites in domestic animals
Effective for onchocerciaris in humans that is caused by Oncocerca volvulus
Scabicide:
compounds used to control mites (Sarcoptes scabiei)
Pediculicide: used
to eliminated head, body and crab lice, fleas
Benzoyl benzoate (benzyl alcohol +
benzoyl chloride): ester from Peru balsam, topical scabicide
Lindane: halogenated hydrocarbon
with insecticidal activity
o A direct poison, fumigant effect, acts as a stomach poison
o Tx of scabies and pediculosis
Crotamiton: topical tx of scabies
Permethrin: synthetic
pyrehtrinoid compound
o Exerts lethal action against lice, ticks, mites and fleas
o Pediculicide for the treatment of headlice
•Which of the following can cause sunburn? A. Amoxicillin
B. Sulfonamindes
C. Macrolides
D.Quinolones
E. Tetracyclines
Board Questions
Antibiotics: natural products
biosynthesized by microorganisms that are toxic to other species of microorganisms.
SYNTHETIC ANTIBACTERIAL AGENTS
Sulfonamides were the first successful selectively toxic antibacterial drugs. _________ was discovered by ______ in 1936, and used to successfully treat puerperal sepsis (childbirth fever) in London. First effective chemotherapeutic agent to cure bacterial infections in humans.
• Sulfonamide toxicities includes the following:
I. Crystalluria II. Rashes III. Nausea A. I only B. II and III C. I and III D. I and II E. I, II and III
Board Questions
H2N
SNH
RO O
1935: era of sulfa drugs
• A bright red dye that was found to create remarkable cures of streptococcal infections:
A. Prontosil
B. Methyl red
C. Methyl orange
D. All
E. None
Board Questions
•Sulfanilamide is: A. a type of sulfonamide B. Same as sulfonamide C. Generic of sulfonamide D. Salt of sulfonamide
Board Questions
Prontosil: brilliant azo red dye which was found to protect against and cure Streptococcal infections in mice; it is converted to its active metabolite “sulfanilamide”
Sulfanilamide is a generic term that denotes: o Aniline-substituted
sulfonamides/sulfanilamides o Prodrugs that generate active sulfanilamides o Non-aniline sulfonamide like mafenide
acetate
Renal toxicity: Older sulfonamides crystallized in urine.
Blood dyscrasias: Hemolytic anemia Dermal toxicity: Rashes, pruritus,
erythema, SJS Rare but serious side effects:
hepatitis, drug-induced fever Less serious side effects: headache, GI
discomfort (nausea, loss of appetite)
Spectrum of activity: G+ and G- bacteria, Nocardia spp. Chlamydia trachomatis, Protozoa, and Enteric bacteria,
ADR: CRANK
Classified according to use: o Oral absorbable (single, mix)
o Oral non-absorbable
o Topical agents
o Sulfanilamide for Intestinal infections, Ulcerative colitis or Redution of Bacterial Flora
Sulfamethizole Sulfisoxazole: Sulfisoxazole acetyl
(prodrug) Sulfisoxazole diolamine: salt form by
adding enough diethanolamine, systemic and local (eye) infection
Sulfamethazine: more soluble in acidic urine
Sulfacetamide: antibacterial
Sulfachloropyridiazine
Sulfapyridine
Sulfamethoxazole
Sulfadiazine
Sulfadiazine sodium: administered as a 5% solution in sterile water IV for patient requiring an immediate high blood level of sulfonamide
Trisulfapyrimidines: oral
suspension and tablet form; contains equal amount of sulfadiazine, sulfamerazine, sulfamethazine
Sulfadoxine & pyrimethamine: tx
of Plasmodium falciparum (pt with chloroquine resistance).
Used for malaria prophylaxis for travellers where chloroquine resistant malaria is endemic
Sulfacetamide sodium: very soluble in water; used as eye drops
Sulfisoxazole diolamine: short to intermiate acting sulfonamide IM, IV
TriSulfa: contains sulfabenzamide, sulfacetamide, sulfathiozole
As a vaginal cream in the tx of Haemophilus vaginalis
Topical sulfonamides for burn therapy:
Mafenide acetate: homologue of the sulfanilamide molecule that is not inhibited by PABA
Effective against Clostridum welchii and for the prophylaxis for wounds
Silver sufadiazine and zinc salt: tx of infection against Pseudomonas spp. a very potent antimicrobial in the treatment of burns, scald and wound infections. Patient acceptance is better than mafenide.
Sulfasalazine: prodrug (m-aminosalicylic acid and sulfapyridine. Effective in treating ulcerative colitis
Trimethoprim: orally active dyaminopyridine structure, closely related to several anti-malarials, a potent antibacterial, tx of uncomplicated UTI
Sulfamethoxazole and Trimethoprim: tx of chronic UTI. DOC for both complicated and uncomplicated UTI especially caused by enterobacteria.
Rationale of the combination?
Reported to be effective against malaria and rickettsial infections.
MOA: same with sulfonamides
Cross resistance to sulfonamides
Mainly use for treating _____________ caused by ______________
Aside from rodents (mice) ________ is another biological test animal to culture M. leprae.
•Drug of choice for leprosy: A. Dapsone
B. Clofazimine
C. Streptomycin
D.Prothionaide
E. Ethionamide
Board Questions
Dapsone, DDS (Avlosulfone®): parent
sulfone and prototype
Treatment of both lepromatous and tuberculoid leprosy
DOC: dermatitis herpetiformis
Sometimes used with pyrimethamine for the tx of malaria and with TMP for PCP
SE: Hemolytic anemia(G6PD), methemoglobinemia, toxic hepatic effects
Widespread disease caused by __________
parasite coined from “mala aria” = bad air
Other names: ague, intermittent fever,
marsh fever, The Fever
Vector: Female Anopheles mosquitos
Parasitic protozoans: Plasmodium vivax
and P. falciparum, P. ovale and P.
malariae (milder, rarely fatal) and P.
knowlesi (zoonotic)
Three potential ways to
control malaria:
Vector control
Drug therapy
Vaccination
NAME DESCRIPTION
Plasmodium falciparum 50% (most common), severe
form, can infect 65% of the
patient’s erythrocytes
Plasmodium vivax 40% very chronic,
recurrence is possible and
can cause reinfection of the
liver cells
Plasmodium malariae 10%, relapses are common
Plasmodium ovale Least common
Figure 7.1 pg. 243
CINCHONA ALKALOIDS Quinine Sulfate: lethal for all
Plasmodium schizonts and gametocytes from P. vivax and P. malariae
Indicated for malaria caused by chloroquine-resistant P. falciparum strains
Used for nocturnal leg cramps
Side Effects: abortifacient
Quinidine: more potent anti-malarial
Stereoisomer of quinine but is primary indicated for cardiac arrhythmias
CINCHONISM
Cinchonism: toxic syndrome
characterized by tinitus, headache, nausea, disturbed vision.
A semi-synthetic anti-malarial agent:
A. Quinine
B. Artemisinin
C. Emetine
D. Cycloguanil
E. Mefloquine
BOARD QUESTIONS
4-AMINOQUINOLINES Chloroquine (Aralen®)
HCl: parenteral; PO4: oral tablet
Main anti-malarial drug for prophylaxis and treatment of malaria
Used also for extra-intestinal amoebiasis
DOC for erythrocytic falciparum malaria, except resistant strain
ADRs: retinopathy, hemolysis, muscle weakness, exacerbation of psoriasis, porphyria, impaired liver function
Hydroxychloroquine (Plaquenil®) High protein bound (remains in the body for
over a month)
4-AMINOQUINOLINES
Amodiaquine Prophylaxis for malaria
Associated with higher incidence of hepatitis and agranulocytosis
Mefloquine (Lariam®)
Schizonticide (newest member)
Exacerbate mental disorders
DOC for malarial supression
8-AMINOQUINOLINES
Primaquine Narrowest spectrum of activity
Most effective against malarial parasite in the liver but not effective against parasites within erythrocytes.
MOA: disruption of parasites mitochondria
DOC: for acute attack of Plasmodium vivax
POLYCYCLIC ANTIMALARIAL DRUGS Doxycycline: a tetracycline that inhibits
the pathogen’s protein synthesis
Prophylaxis for malaria
CI in children and in areas with greatest sunlight
Halfantrine: can arrest tissue
conduction in cardiac muscles
Lumefantrine: proposed MOA:
inhibition of β- hematinin by forming complex with hemin
POLYCYCLIC ANTIMALARIAL DRUGS
Quinacrine: most toxic
antimalarial drug
Acridine dye (can cause yellow color of skin, tissues, etc.)
Treatment for malaria and a sclerosing agent
Artemisinin
FIXED COMBINATION
Sulfadoxine + Pyrimethamine (Fansidar®)
Prophylaxis and treatment of chloroquine resistant malaria
MOA: inhibition of folic acid biosynthesis and dihydrofolate reductase
FIXED COMBINATION Atovaquone and Proguanil
(Malarone®)
Effective against erythrocytic and exoerythrocytic plasmodium
Used for resistant malaria
MOA: inhibition of dihydrofolate reductase and damage to the parasite’s mitochondria
Proguanil is a prodrug of _________
Artemether and Lumefantrin:
interfere heme metabolism interfere parasites in erythrocytic stage
NEW DRUG APPROACHES
Inhibition of non-mevalonate pathway
Fosmidomycin: isolated from
Streptomyces fermentation broth in 1980.
Inhibits the enzyme DOXP reductoisomerase
Inhibition of Glutathione reductase
Which of the following best described antibiotics?
I. It is a product of metabolism
II. It is a synthetic product produced as a structural analogue of a naturally occurring antibiotic (a biosynthetic product)
III.It antagonizes the growth or survival of one or more species of microorganism
IV.If it is potent, it is effective at low concentration
Antibacterial Antibiotics
• Villemin’s “antibiosis”: concept of survival of the fittest
• Waksman: an antibiotic or antibiotic substances is a substance produced by microorganism which has the capacity of inhibiting the growth and even destroying other microorganisms
Attributes of a good antibiotics, except: I. Exhibit sufficient selective toxicity
II. Chemically stable
III.Slow rates of biotransformation and rapid rates of elimination
IV.Has narrow spectrum of activity to avoid toxicity
Which is true about the MOA of antibiotics?
I. Inhibition of bacterial cell wall is a good sign of selective toxicity
II. Competitive antagonist of pathogen’s metabolite
III.Inhibition of pathogen’s protein synthesis
IV.Inhibition of the integrity and function of microbial cell membrane
EXAMPLES OF SELECTIVE ACTION
•Anti-infectives agent that target ribosomes are said to be : A. Bacteriostatic/Fungistatic
B. Pancidal
C. Bactericidal/Fungicidal
Board Questions
Site of Action Antibiotic Type of Activity
Cell Wall Bacitracin Bactericidal
Cephalosphorins Bactericidal
Penicillins Bactericidal
Vancomycin Teicoplanin
Bactericidal
Cell Membrane Amphotericin B Fungicidal
Nystatin Fungicidal
Ribosomes 50s
CMC Bacteriostatic
Erythromycins Bacteriostatic
Lincomycins Bacteriostatic
Site of Action Antibiotic Type of Activity
30s AmiNOglycosides Bacteriostatic
TCN Bacteriostatic
Nucleic acids Actinomycin Pancidal
Griseofulvin Fungistatic
Drug Process affected
Type of Activity
Mitomycin C DNA synthesis Pancidal
Rifampin mRNA synthesis Bactericidal
Question
•Which of the following is/are example/s of beta-lactam antibiotics?
I. Penicillins
II.Beta lactamase inhibitors
III.Cephalosporins
IV.Monobactams
• Which of the following is not an example/s of beta-lactam antibiotics?
A. Penicillins B. Beta lactamase inhibitors C. Cephalosporins D. Monobactams E. Quinolones
Board Questions
Development of Penicillin
• Earliest known antibiotic (historical prototype)
• Sources (2) • Has beta-lactam thiazolidine ring • Derivative of 6-aminopenicillanic acid
(6-APA)
• Benzylenicillin and early cephalosporins mainly active against gram positive bacteria.
• “Broad spectrum” penicillin appeared: ampicillin, ureidopenicillins and cephalosporins: cefuroxime, cefotaxime
• Carbapenems and latest generation of cephalosporins, e.g ceftazidime more active against gram negatives.
Development of Penicillin
Mnemonics
• FOR GRAM POSITIVE BACTERIA:
• Corny Actors KNock Back Listerine in the Closet
• Corynebacteria, Actinomyces, Nocardia, Bacillus, Listeria, and Clostridium. (plus Staph, and Strep - the t looks like a + sign)
Benzylpenicillin: Main Indications • Strep. pyogenes sepsis (from sore throat
to fasciitis)
• Pneumococcal pneumonia, meningitis
• Meningococcal meningitis, sepsis
• Infective endocarditis (Strep spp.)
• Strep. group B sepsis
• Diphtheria
• Syphilis, leptospirosis
Organisms producing TEM1beta lactamase • Haemophilus influenzae
• Neisseria gonorrhoeae
• Bacteroides fragilis
• Staphylococcus aureus
• Escherichia coli
Penicillins and related products are generally safe but… • Allergic reactions: Rashes
• Hypersensitivity: Urticaria immediately after penicillin after a further dose of any penicillin or cephalosporin
• Most severe reaction: Anaphylaxis
• Anaphylaxis: allergy of respiratory system characterized by diffuclty in breathing
• Antidote: EPI
• Patient taking amoxicillin experience rashes after taking it orally, what might be the best alternative to penicillin? A. Aureomycin B. Erythromycin C. Lincomycin D. Spectinomycin E. All of these
Board Questions
What antibiotics can be used in penicillin allergy (substitute)? • Macrolides: erythromycin,
clarithromycin (mainly gram positive)
• Quinolones: ciprofloxacin, levofloxacin (mainly gram positive)
• Glycopeptides (serious infections)
• Fusidic acid, rifampicin, clindamycin (mainly gram positive)
Remember what are the other beta lactams:
• All penicillins: ampicillin, augmentin, piperacillin, cloxacillin
• Cephalosporins: cefuroxime, cefotaxime, ceftriaxone, ceftazidime (5-10% cross sensitivity)
• Monobactam: aztreonam (low cross sensitivity)
• Carbapenems: imipenem, meropenem
•Which of the following is a depot penicillin preparation? A. Penicillin G Benzathine
B. Benzylpenicillin
C. Methicillin
D.Phenoxymethylpenicillin
E. Cloxacillin
Board Questions
Natural/Biosynthetic Penicillins • Penicillin G
• Penicillin G Procaine: a repository form (depot)
• Penicillin G Benzathine: a depot form
• Phenoxymethylpenicillin: first synthetic penicillin
Pen G Sodium 1mg = 1667 units Pen G Procaine 1mg = 1009 units Pen G K+ 1mg = 1530 units
Penicillinase-sensitive
• PenG
• PenV
• Ampicillin
• Amoxicillin
• Carbenicillin
• Mezlocillin
• Ticarcillin
• Piperacillin
Penicillinase – resistant
• Narrow spectrum of activity
• Active against G+ cocci
• Methicilllin: 2nd synthetic can cause interstitial nephritis
• Nafcillin
• Oxacillin
• Cloxacillin
• Dicloxacillin
Isoxazoyl penicillin
Broader spectrum penicillins (α-amino group)
• Ampicillin: agent of choice for
Haemophilus influenza infections with probenecid used for gonorrhea
• Bacampicillin HCl: prodrug
• Amoxicillin: a p-hydroxy analog of
ampicillin cover most organisms hit by penicillin but also E. coli, some Proteus (cause UTI’s)
Broader spectrum penicillins (α-amino group)
• Augmentin stable to TEM1 β-lactamase because of the clavulanic acid therefore more active than ampicillin
• Tazocin: broader coverage than Augmentin against gram negatives including Pseudomonas
Extended Spectrum Penicillins • Carboxypenicillins
▫ Carbenicillin (disodium and indanyl sodium salts): UTI
▫ Ticarcillin: isostere of carbenicillin
▫ Has greater potency against P. aeruginosa and Bacteroides
• Acylureidopenicillins ▫ Mezlocillin
▫ Piperacillin
• Penicillin is the drug of choice for the following anti-infective conditions, except:
A. Gonococcal infection
B. Pneumococcal infection
C. Treponema infection
D. Streptococcal infection
E. Pseudomonal infection
Board Questions
Acid Sensitive
• PenG
• Methicillin
• Carbenicillin
• Mezlocillin
• Ticarcillin
• Piperacillin
Acid Resistant
• Penicillin V
• Ampicillin
• Amoxicillin
• Nafcillin
• Oxacillin
• Cloxacilin
• Dicloxacillin
β-lactamase inhibitors
B-lactamase inhibitors
• Class I inhibitors “suicide substrates” ▫ Clavulanic acid (has a strained beta-
lactam ring and has no amino acyl side chain compared to other B-lactam antibiotics) from Strep. clavugeris
▫ Sulbactam ▫ Tazobactam: a penicillanic acid
sulfone
•Class II inhibitors: “carbapenems” ▫ Thienamycin from ___________ ▫ Imipinem – cilastatin (inhibitor of
________) ▫ Ertapenem: is a synthetic 1-beta-
methylcarbapenem. ▫ Meropenem ▫ Biapenem
β-lactamase inhibitors
2nd generation carbapenems
Carbapenems: sensitive to dehydropeptidase I • Absence of sulfur atom in the bicylic ring
system
• It has no aminoacyl side chain
• Active against many highly penicillin resistant-strains of pneumonococci.
• Beta-lactam of choice for the treatment of enterobacter infections.
• SE: N & V, diarrhea, skin rash, renal failure (Imipinem), seizures
Carbapenems: sensitive to dehydropeptidase I • Imipenem + Meropenem and Biapenem:
have a very broad spectrum activity against gram-negative bacteria, anaerobes, Streps.
• Now used to treat gram negative infections due to so called ESBL producing organisms e.g. E. coli, Klebsiella
• Ertapenem is a new member of the group but its not active against Pseudomonas
Drug Combination
•Co-amoxiclav
•Primaxin®
•Tazocin®
•Unasyn ®
•Co-trimoxazole
Background: Cephalosporins • Discovered by Guiseppe Brotzü in 1945
from ___________________
• Abraham and Newton discovered three principal antibiotic components as:
• Cephalosporin P1 (steroidal type)
• Cephalosporin N/Penicillin N (Gram negative> Gram positive)
• Cephalosporin C (dihydrothiazine ring)
Adverse Reactions
• Hypersensitivity: rashes, anaphylaxis, cross-sensitivity
• Diarrhea: disruption of normal flora
• Nephritis: Methicillin
• Hemorrhage: anti-pseudomonal
• Electrolyte disturbance
Drug Interactions
• with Probenecid: inhibit renal excretion of penicillin (potentiation)
• with Aminoglycosides: penicillin increase entry (synergism): may form inactive complex if mixed in infusion fluid
• With –static drugs antagonism
• Contains beta-lactam dihydrothiazine ring
• Derivative of 7-aminocephalosporanic acid
Background: Cephalosporins
• Cefuroxime: surgical prophylaxis
• Cefotaxime/ceftriaxone: meningitis nosocomial infections excluding Pseudomonal infection
• Ceftazidime: nosocomial infections including Pseudomonal
Cephalosporins: main uses
Classification
Activity G+ (H) Activity G- (L)
1st generation Highest Lowest
2nd generation Low Lower
3rd generation Lower Higher
4th generation Lowest Highest
Oral Cephalosporins
• Cephalexin
• Cephradine (Parenteral)
• Cefadroxil
• Cefaclor
• Loracarbef (1st,
carbacephems)
• Cefprozil
• Cefuroxime (Parenteral)
• Cefpodoxime
• Cefixime
• Ceftibuten
Parenteral Cephalosporins
• Cephradine (Oral)
• Cephalothin
• Cephapirin
• Cefazolin
• Cefamandole
• Cefonicid
• Ceforanide
• Cefoxitin
• Cefotetan
• Cefmetazole
• Cefuroxime (Oral)
• Cefoperazone
• Cefotaxime
• Ceftizoxime
• Ceftriaxone
• Ceftazidime
• Cefepime
• Cefpirome
• Which of the following is an example of 2nd generation cephalosporins?
I. Cefalexin II. Cefuroxime III. Cefaclor A. I and II only B. I and III C. II and III only D. II only E. III only
Board Questions
Cephalosporin Mnemonics 1st Gen 2nd Gen 3rd Gen 4th Gen 5th Gen
“Ceph” Except:
Cefadroxil Cefazolin
“Cef” DO NOT END in –one and –ime except: Loracarbef
Cefpodoxime
End with –one and –ime
except: Ceftibuten
Moxalactam
Cephalexin Cephalotin Cephapirin Cephradine
*Cefuroxime Cefaclor
Cefamandole Cefonicid Cefotetan Cefoxitin
Cefmetazole Cefprozil
*Cefuroxime Ceftazidime Ceftizoxime Ceftriaxone
Cefixime
Cefoperazone Cefotaxime
Cepefime Cefpirome Cefoselis Cefcidin
Ceftobiprole Ceftaroline
First Generation Cephalosporins • Very active against Gram-positive
cocci. • Inactive against MRSA strain of
Staph., E.coli, K. pneumoniae, P. mirabilis
• DO NOT CROSS BBB • Broad spectrum, nontoxic • First generation: PEcK
Second Generation Cephalosporins • Active against organisms inhibited by
first-generation, has extended Gram-negative coverage
• Cannot pass BBB
• Not active against enterococci or P. aeruginosa
• Second generation: HENPEcK
Third Generation Cephalosporins • Has extended Gram-negative
coverage; some products can pass BBB • Active against Citrobacter, Providencia • Effective against beta-lactamase
producing strain of Hemophilus and Neisseria
• Third generation: HENPEcKSSS
Fourth Generation Cephalosporins • More resistant to hydrolysis by
chromosomal beta-lactamase • Has good activity against P.
aeruginosa, Enterobacter, S. aureus, and S. pneumoniae
• Fourth generation: P. aeruginosa
Fifth Generation Cephalosporins
•Enterococcus faecium
•Staphylococcus aureus
•Klebsiella pneumoniae
•Acinetobacter baumanii
•Pseudomonas aeruginosa
•Enterobacter spp
Monobactams
• Relatively resistant to beta-lactamases and active against Gram-negative rods
• No activity on Gram-positive and anaerobes
Monobactams
• Aztreonam: poor oral bioavailability, relatively non-toxic
• Tigemonam: orally active monobactam
• Which of the following statements is not true regarding the aminoglycosides antibiotics? A. they are highly ionized in solution B. they are antibactericidal C. they are more effective in alkaline
medium D. they are ototoxic and nephrotoxic E. they are easily absorbed after oral
administration
Board Questions
AmiNOglycosides
• Contain an amino sugar that are linked by ______
• Contain a highly substituted 1,3-diaminocyclohexane central ring ▫ Deoxystreptamine (KNGT)
▫ Streptadine
• Potent, broad-spectrum activity
• Strongly basic (sulfates)
AmiNOglycosides
• Mainly active against gram negative bacteria
• Mainly used to treat nosocomial infections: pneumonia in ITU, septicaemia
• Can cause neuromuscular blockade
• Also used in combination
AmiNOglycosides
• Ototoxic esp. when used with furosemide
• Nephrotoxic
• Neuromuscular blockade ( dec. Acetylcholine release, can be managed by Ca gluconate, neostigmine)
• Synergistic effect with beta-lactams
• Antagonistic with CMC
ADR: AmiNOglycosides
• Streptomycin: first anti-TB antibiotic from Strep. griseus
• Neomycin: from Strep. fradiae (orally active)
• Paromomycin: Strep. rimosus anti-amebic
• Kanamycin: Strep. kanamyceticus, tx for bacillary dysentery
AmiNOglycosides
• Amikacin: semi-synthetic, 1-N-amino-a-hydroxybutyrylkanamycin
• Gentamicin: from Micromonospora purpurea (cream, ung.)
• Tobramycin: most active nebramycins, obtained from Strep. Tenebrarius, useful for conjunctivitis
AmiNOglycosides
• Netilmicin: 1-N-ethylsisomicin • Sisomicin • Spectinomycin: aminocyclitol
antibiotic
AmiNOglycosides
•Tetracycline is: A. An intermediate spectrum,
bactericidal
B. A broad spectrum, bacteriostatic
C. A broad spectrum. Bactericidal
D.An intermediate spectrum, bacteriostatic
Board Questions
Tetracyclines
• Broad spectrum, -static • Binds to 30s • Isolated from Streptomyces or
synthetically prepared • Derivatives of
“octahydronaphthacene” • Amphotheric and zwitterions • Can chelate metals
Classification of Tetracyclines
• Short – Acting: ▫ Tetracycline ▫ Oxytetracycline
• Intermediate Acting: ▫ Demelocycline ▫ Lymecycline
• Long – Acting: ▫ Doxycycline ▫ Minocycline
•Tetracycline: most popular
•Rolitetracycline: condensation
product of tetracycline
•Chlortetracycline: bright yellow
color
•Oxytetracycline
•Methacycline
Tetracyclines
•Demelocycline: 7-chloro-6-
demethyltetracycline
•Melocycline •Doxycycline: least phototoxic
among TCNs
•Minocycline: most potent
tetracycline • Tigecycline: first glycylcycline
Tetracyclines
Activity: Tetracyclines
• Effective for Chlamydia, Mycoplasma, Pneumonia, Rocky mountain spotted fever, Lyme’s disease, Cholera, H. pylori
Structure of Tetracyclines
Tetracycline SE
• Gastric distress
• Yellowing of teeth
• Bulging fontanel
• Phototoxicity
• Liver damage
• Affects renal function
• Which of the following is used for leptospirosis and malaria?
A. Metronidazole
B. Euphorbia hirta
C. Doxycycline
D. Penicillin
E. Dactinomycin
Board Questions
• Class of antibiotics which has large lactone ring, has a ketone group and has glycosidically linked amino sugar:
A. Penicillin
B. Cephalosporins
C. Aminoglycosides
D.Macrolides
Board Questions
Macrolides
• Isolated from Actinomycetes
• Binds 50s, -cidal at high dose
• Chemical characteristics: ▫ Large lactone ring
▫ Ketone group
▫ Glycosidically linked amino sugars
• Spectrum of activity: same with PCNs
Structure of Macrolides
Macrolides
•Erythromycin •Erythromycin estolate: lauryl
sulfate, Ilosone • Erythromycin lactobionate:
erythromycin base is reacted with lactobiono-sigma-lactone
• Clarithromycin: 6-methyl ether of erythromycin,
Macrolides
•Azithromycin: semi-synthetic
derivative of erythromycin, prototype of the azalides:
• Dirithromycin lactobionate: more soluble prodrug of 9S-erythromycyclamine
• Troleandomycin: a triacetyl derivative of oleandomycin
Macrolides: SE
•GIT disturbances
•Jaundice or cholestatic hepatitis
•Thrombophlebitis • Inhibits cytochrome P450
• DI: Terfenadine and astemizole: arrhythmia
•Which of the following contains sulfur?
A.Lincomycin
B.Clindamycin
C.Clarithromycin
D. Penicilllin G
Board Questions
Lincomycins
•Lincomycin: contains a
pyrrolidine nitrogen.
•Clindamycin: 7-chloro-7-deoxy-
lincomycin
Polypeptides
• Describe as cyclic peptides
• Most powerful bactericidal antibiotics characterized by presence of sever –CONH linkages
• SE: neurotoxicity and nephrotoxicity
Polypeptides
•Vancomycin: from Strep.
orientalis DOC for Pseudomembranous colitis (PO)
• ADR: “red-man” syndrome: flushing due to histamine release caused by rapid infusion
Polypeptides
• Teicoplanin: Actinoplanes teichomyceticus
• MOA: inhibitor of cell wall synthesis affecting peptidoglycan layer
• Bacitracin: from Bacillus subtillis enhance activity with zinc
• Polymyxin B: Bacillus polymyxa
Polypeptides
• Colistin: Aerobacillus colistinus
• Colismethane sodium
• Gramicidin: from tyrorthricin, act as tunnelling molecule that act on the plasma membrane and result in the uncontrolled movement of ions across cell membrane leading to cell death. Isolated from Bacillus brevis
• Which of the following chemotherapeutic agents has a good penetrability into the cerebrospinal fluid?
A. Cephalexin
B. Chloramphenicol
C. Streptomycin
D. Tobramycin
E. Gentamicin
Board Questions
Unclassified Antibiotics
•Chloramphenicol: with nitro
group • DOC for typhoid fever • ADRs: gray-baby syndrome, blood
dyscrasias
ADR of Chloramphenicol
• Hemolytic anemia: G6PD deficient
• Aplastic anemia
• Gray-baby syndrome (cyanosis), blood dyscrasias
• Inhibits CYP450
Unclassified Antibiotics
•Novobiocin: topical use
• Mupirocin: topical use
• MOA: interference with RNA and protein synthesis
• Quinupristin/Dalfopristin (30:70)
Unclassified Antibiotics
• Linezolid: an oxazolidinedione that can prevent the formation of 70s ribosome by binding to the 50s subunit
• Fosfomycin tromethamine
Some other antibiotics occasionally used
• Co-trimoxazole
• Chloramphenicol (typhoid fever, meningitis)
• Colistin (resistant Pseudomonas) topical
• Neomycin: GUT decontamination, topical
Antibiotics for PUD
•Amoxicillin
•Clarithromycin
•Metronidazole (anti-protozoal)
•Tetracycline
Drug of Choice
• Listeria monocytogenes
• Salmonella
• Shigela spp.
• Meningitis
• ANSWER: A _ _ _ _ _ _ _ _ N
Gram +
• Clostridium perfringens • Cause: ______
• Treponema pallidum • Cause: ______
• ANSWER: ____________ • Clue: aka Benzylpenicillin
Drug of Choice
•MRSA
•MRSA means _____________
•ANSWER: V__________
Drug of Choice
• for SURGICAL PROPHYLAXIS
• ANSWER: Cefa____ injection
• Reason: used because of high bone
penetration and because it’s a good alternative to anti-staph penicillin in penicillin – allergic patients.
Drug of Choice
• for Enterococcus • ANSWER: G__________
• for Chlamydia trachomatis • ANSWER: A__________
• for Nocardia and Pneumocystis
pneumonia • ANSWER: Co__________
Drug of Choice
• for Clostridium tetani • ANSWER: V__________
• for Neisseria gonorrhea • ANSWER: Ceftriaxone and Cefixime
• for Typhoid d/t Salmonella • ANSWER: Ceftriaxone
First Line Agent/s
• in treating penicillin resistant pneumonococci
• ANSWERS: Ceftriaxone, Cefotaxime and Vancomycin
First Line Agent/s
• for systemic Pseudomonas aeruginosa
• ANSWERS: ▫ Ticarcillin ▫ Piperacillin ▫ Ceftazidime ▫ Cefepime ▫ Tobramycin
First Line Agent/s
• for Nocardia • ANSWER: M__________
• for Helicobacter pylori • ANSWER: T__________
• for Vibrio spp. • ANSWER: D__________
First Line Agent/s
• for Brucella • ANSWER: D_________ + G________
• for Helicobacter pylori, Viridans
streptococci, Strep. agalactiae, Listeria meningitis, Campylobacter
• ANSWER: _ E _ _ _ M I C I N
First Line Agent/s
• Question: What are the two penicillin-derived drugs that are extended spectrum for Pseudomonas infections? (First line and Broadest spectrum)
• Answers: ▫ First Line: Ticarcillin and derivatives
▫ Broadest spectrum: Piperacillin and derivatives with Tazobactam
•Question: What is the first line
agent used to treat mixed intra-abdominal infections by Bacteriodes?
•Answers: ▫ Cefoxitin
• Question: What is the first line agents used to treat Haemophilus influenzae?
• Answers: ▫ Ceftriaxone
▫ Cefotaxime
• Question: How do you treat antibiotic induced enterocolitis d/t Staph. aureus or Clostridium difficile?
• Answers: ▫ Vancomycin PO
▫ Why PO? Because it is poorly absorbed orally and will therefore be very active against Gram + bacteria in the intestine causing colitis.
•Most importance specie as a source of anti-microbial agents: A. Actinomyces B. Streptomyces C. Penicillium D.Streptococci E. Tropane alkaloids
Board Questions
Name of the Drug SOURCE
Streptomycin Streptomyces griseus
Clavulanic acid Streptomyces clavugeris
Thienamycin Streptomyces cattleya
Erythromycin Streptomyces erythreus
Lincomycin Streptomyces lincolnensis
Chlortetracycline Streptomyces aureofaciens
Neomycin Streptomyces fradiae
Kanamycin Streptomyces kanamyceticus
Gentamicin Micromonospora purpurea
Oxytetracycline Streptomyces rimosus
Name of the Drug SOURCE
Vancomycin Streptomyces orientalis
Bacitracin Bacillus subtilis
Gramicidin Bacillus brevis
Chloramphenicol Streptomyces venezuelae
Rifamycins Streptomyces mediterranei
Griseofulvin Penicillium griseofulvum
Amphotericin B Streptomyces nodosus
Nystatin Streptomyces noursei
Natamycin Streptomyces natalensis
Tobramycin Micromonospora tenebrarius
Anti-viral Agents
• Virus: smallest self-replicating
organisms
INFECTION PROCESS OF A VIRUS
Adsorption Entry Uncoating Transcription Translation
Assembly Release
Adsorption Entry Uncoating Transcription Translation
Assembly Release
Classification of Viruses
• Nucleic acid: DNA or RNA viruses
• Viral morphology: helical or icosahedral
• Site of replication: cytoplasm or nucleus
• Coating: enveloped or non-enveloped
• Serological typing: antigenic signatures
• Cell type infected: B-lymphocytes or T-lymphocytes
TARGETS FOR ANTI-VIRAL DRUGS
TARGETS OF ANTIVIRALS
1. VIRAL ENVELOPE/CAPSULE • Primary Targets for
antibodies
1. VIRAL ENVELOPE/CAPSULE • Primary Targets for antibodies
2. ATTACHMENT • Receptors may be blocked
(sialic acid derivatives, ligands or anti-receptor antibodies)
• The process of production is poorly understood and kinetic parameters are not well defined.
TARGETS OF ANTIVIRALS
3. PENETRATION / UNCOATING • Uncoating is largely mediated
by cellular enzymes, • Penetration, is often influenced
by one or more virus proteins
• For Influenza virus, inhibition of M2 protein prevents viral penetration by inhibiting membrane fusion.
NAM – N-acetylmuramic acid
Hemmaglutinin
M2 Proteins
PENETRATION
UNCOATING
TARGETS OF ANTIVIRALS
1. VIRAL ENVELOPE/CAPSULE • Primary Targets for antibodies
2. ATTACHMENT • Receptors may be blocked
(sialic acid derivatives, ligands or anti-receptor antibodies)
4. REPLICATION • Targets various polymerases
(HIV) • Serve as polymerase substrates
to terminate replication. (nucleoside analogues)
ACYCLOVIR
TERMINATION OF THE DNA/RNA STRAND
• Most nucleoside analogues are Pro-drugs: requires viral polymerase, NOT cell polymerase
TARGETS OF ANTIVIRALS
1. VIRAL ENVELOPE/CAPSULE 2. ATACHEMENT 3. PENETRATION/UNCOATING
Chemoprophylaxis: Adamantanamines
• MOA: prevent viral uncoating and interferes viral assembly
• Amantadine: blocks viral ion channel M2 protein
• Rimatadine: methylated-amantadine
Chemoprophylaxis: Neuraminidase inhibitors
• Sialic acid analogs
• Zanamivir: Bronchospasms
• Oseltamivir : N & V
• Important cytokines that possess antiviral, immunomodulating and anti-proliferative action
• MOA: inhibition of viral penetration or uncoating, synthesis of mRNA, translation of viral proteins, assembly and release
Chemoprophylaxis: Interferons
• Three classes of interferons – α , β, γ
• Indication: Venereal warts (Condyloma acuminatum), chronic hepa B and C, Kaposis sarcoma, MS
• PEG – Interferon: 40 kDa, advantage of sustained delivery and reduced clearance of interferon
Chemoprophylaxis: Interferons
• α and β interferons are produced by all the cells in response to viral infections. Effective against HBV, HCV and HPV.
• γ interferons are produced only by T lymphocyte and NK cells in response to cytokines – immune regulating effects
• γ has less anti-viral activity compared to α and β interferons
Chemoprophylaxis: Interferons
Nucleoside antimetabolites • Inhibitors of DNA polymerase
• Reverse transciptase inhibitors
• Miscellaneous (Ribavirin): used for
sever LRTI cause by RSV in carefully selected hospitalized infants and young children
DNA Polymerase inhibitors
•Idoxuridine: iodinated analog of
thymidine, non-selective, tx of herpes simplex keratitis
•Trifluridine: fluorinated analogue
of thymidine, tx of primary keratoconjunctivitis and recurrent epithelial keratitis due to HSV 1 and 2
DNA Polymerase inhibitors
•Vidarabine: 2’epimer of natural
adenoside, broad spectrum, alternative for idoxuridine
•Cytarabine: MOA: blocks cellular
utilization of deoxycytidine, hence inhibiting the replication of viral DNA
DNA Polymerase inhibitors: Acyclovir Congeners
•Acyclovir (nucleoside analog of
2’deoxyguanosine)
• and Valacyclovir (L-valyl ester
prodrug): DOC for Varicella zoster, chicken pox
• Ganciclovir: Analogue of acyclovir with an additional HYDROXYMETHYL GROUP on the acyl side chain.
• tx and supression of sight threatening CMV retinitis in immunocompromised patients
DNA Polymerase inhibitors: Acyclovir Congeners
•Famciclovir: diacetyl prodrug of
penciclovir
•Penciclovir: tx of recurrent
Herpes labialis. used only topically whereas Famciclovir can be administered orally.
DNA Polymerase inhibitors: Acyclovir Congeners
DNA Polymerase inhibitors • Cidofovir: monophosphate nucleotide
analogue of dCTP; tx of CMV retinitis in AIDS patient. AE: renal impairment
• Foscarnet: 2nd line drug for the
treatment of CMV retinitis in AIDS patients; trisodium phosphonoformate: organic analogue of inorganic pyrophosphate
DNA Polymerase inhibitors • Adefovir dipivoxil: DOC for
chronic Hepatitis B • Ribavirin: a guanosine analog,
inhibits RNA polymerase and reverse transcriptase. DOC for RSV bronchiolitis
Board Questions
• Drugs used for herpes virus infection include the following, except:
A. Oseltamivir
B. Foscarnet
C. Ganciclovir
D. Idoxuridine
E. Aciclovir
Reverse Transcriptase Inhibitors
•Zidovudine (AZT): a thymidine
analogue; SAR: 3’ azido group prevents the formation of 5’3’-phosphodiester bond, causing DNA termination
• recommended for the management of adult patients with symptomatic HIV infection with history of PCP
Reverse Transcriptase Inhibitors • Didanosine: a guanine analog,
recommended for AZT intolerant advanced HIV infection
• Zalcitabine: cytosine analog, combined with AZT for the treatment of advance HIV infection
Reverse Transcriptase Inhibitors • Lamivudine: contains sulfur atom
instead of a methylene group • Stavudine: thymidine analog. ADR:
peripheral neuropathy
Agents for HIV infection
• HIV – Vaccine ▫ Generally safe and elicit a protective immune
response ▫ Stimulate both cellular and humoral immunity ▫ Protect components against all major HIV
subtypes ▫ Induce long lasting protection ▫ Induce local immunity ▫ Practical for worldwide delivery and
administration
Agents for HIV infection
• Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ▫ Nevirapine ▫ Delaviridine ▫ Efavirenz: widely use NNRTIs
• Common side effect: RASHES
Agents for HIV infection
•HIV Protease inhibitors ▫ Saquinavir ▫ Indinavir ▫ Ritonavir ▫ Amprenavir ▫ Nelfinavir
• Common side effect: Weight gain, dyslipidemia, hyperglycemia
New agents for HIV infection
• HIV entry inhibitors • Chemokine Receptor binders • Inhibitors of GP41 Fusion
activity • Integrase inhibitors (Raltegravir) • siRNA • CCR5 & CXCR4 • T20 (Pentafuside)
Anti-neoplastic Agents • Drugs intended for the treatment of cancer
• Cancer: are abnormal cells
characterized by tumors which are then characterized as malignant.
• Two types of tumors: ▫ Benign: non-cancerous
▫ Malignant: cancerous
• One gram of tumor is equivalent to _____________
• A very common adverse reaction of alkylating agents used in the treatment of cancer:
A. Bulging fontanel
B. Steven Johnson’s Syndrome
C. Mydriasis
D. Ataxia
E. Alopecia
Board Questions
COMMON SIDE EFFECTS ASSOCIATED TO ANTICANCER AGENTS
Alkylating agents (Nitrogen Mustards)
• Agents that replace hydrogen with an alkyl group (by substitution). Forms adducts causing DNA strand breakage.
• Thiotepa: mainstay therapy for solid
tumors when followed by autologous bone marrow transplantation
• Mechlorethamine: a dialkylating agent,
DOC for Hodgkin’s disease
• Ifosfamide: for germ cell testicular cancer
Alkylating agents (Nitrogen Mustards)
• Busulfan: “causes sulfur stripping”
• Cyclophosphamide: cell cycle non-
specific, phosphoramide mustard (major metabolite)
• Melphalan: for multiple myeloma
• Chlorambucil: first line agent for chronic
lymphocytic leukemia and macroglobulinemia
• Bendamustine (Merck Manual,table 124-3)
•Mechanism of action: •Establishes cross-links within and
between DNA strands
Alkylating agents (Organoplatinum)
•Cisplatin: most reactive and most
effective in platinating DNA
•Carboplatin: administered with
1,1-cyclobutane-dicarboxylate to reduce toxicity
•Oxaliplatin: activated in low-
chloride environment, not recognized by MMR
Alkylating agents (Organoplatinum)
• Alkylates DNA with restricted uncoiling and replication of strands.
• Lomustine: first line for metastatic brain tumor and second line for recurring Hodgkin’s disease
• Carmustine: used for brain tumors (can penetrate BBB)
Alkylating agents (Nitrosoureas)
Alkylating agents
• Procarbazine: for Hodgkin’s lymphoma
• Dacarbazine and Temozolomide: form DNA adducts
• Altretamine: involves in hydroxylation of methyl group
• Streptozocin: useful in inducing hyperglycemia on animal model; from Strep. achromogenes subsp. Strepzoticus
• Which of the following antineoplastics is not considered an anti-metabolite? A. Cytarabine B. Methotrexate C. Etoposide D. Thioguanine E. Fluorouracil
Board Questions
Anti-metabolites
• Compounds closely related in structure to a cellular precursor (N-base), act as “imposter” that is capable of preventing the proper use of these natural cellular precursor
• MOA: prevention of biosynthesis or use of normal cellular metabolites by enzyme inhibition
Anti-metabolites (Folates)
• Folates (anti-folates): designed to interact
at cofactor sites for enzymes involved in the biosynthesis of nucleic acid bases.
• Methotrexate: first drug to produce
substantial remissions in leukemia esp. ALL binds to dihydrofolate reductase and interferes with TS
• Pemetrexed: a pyrrolopyrimidine analog.
MOA: inhibition of TS
Anti-metabolites (Folates)
• Trimetrexate: non-classical folate
antagonist that is structurally similar to MTX. Inhibits enzyme dihydrofolate reductase and has been approved for the treatment of Pneumocystis carinii pneumonia in patient with HIV/AIDS.
• Hydroxyurea: MOA: inhibition of
ribonucleotide reductase
•6-mercaptopurine: (blokcks de
novo purine synthesis) primary treatment for acute leukemia together
with 6- thioguanine • MOA: incorporation of the
triphosphate metabolite into DNA/RNA
Anti-metabolites (Purine)
•Fludarabine: Useful of chronic
lymphocytic leukemia and non-Hodgkin’s lymphoma. Inhibits DNA synthesis and inhibits ribonucleotide reductase.
Anti-metabolites (Purine)
•Cladribine: a deoxyadenosine
analog for hairy cell leukemia. MOA: incorporation into DNA causing inhibition of DNA chain extension and inhibition of DNA synthesis and function. Inhibits ribonucleotide reductase
Anti-metabolites (Purine)
• Vidarabine
• Clofarabine: Inhibits DNA synthesis
• Pentostatin: MOA: inhibition of adenosine deaminase increase dATP (cytotoxic to lymphocytes).
• Nelarabine and Pentostatin: inhibits DNA synthesis
Anti-metabolites (Purine)
• 5-FU: palliative treatment of carcinoma of the breast, colon, pancreas, rectum and stomach. MOA: inhibition of TS by the deoxyribose monophosphate metabolite.
Anti-metabolites (Pyrimidine)
• Floxuridine (FUDR): a fluopyrimidine deoxynucleoside analog used to treat GI adenocarcinoma metastatic to the liver. MOA: converted to 5-FU inhibition of TS disrupting DNA synthesis, function and repair.
Anti-metabolites (Pyrimidine)
• Capecitabine: a fluoropyrimidine carbamate prodrug of 5-FU used for metastatic breast and colorectal cancer. MOA: converted to 5-FU by thymidine phosphorylase esterase activity to hydrolyze the carbamate moiety and deamination.
Anti-metabolites (Pyrimidine)
•Gemcitabine: a fluorine-substituted
deoxycytidine analog, inhibit DNA synthesis and function via DNA chain termination, a potent radiosensitizer.
• DOC for locally advanced or metastastic adenocarcinoma of the pancreas; with cisplatin. DOC for inoperable locally advanced or metastatic NSCLC.
Anti-metabolites (Pyrimidine)
• Cytarabine: a cytosine arabinoside from Cryptothetya crypta treatment for acute agranulocytic leukemia. Activated into ara-CTP which is then incorporated to DNA chain causing chain termination and inhibition of DNA synthesis
• 5-Azacytidine, Decitabine, Tegafur
Anti-metabolites (Pyrimidine)
• The following antibiotic possess clinically useful anti – malignant property, except:
A. Streptomycin
B. Daunorubicin
C. Mitomycin
D. Plicamycin
E. Bleomycin
Board Questions
Antineoplastic - Antibiotic • Actinomycins: Dactinomycin/
Actinomycin D
• Anthracycline: Doxorubicin, Daunorubicin, Idarubicin, Epirubicin and Valrubicin
• Glycopeptide: Bleomycin
Antineoplastic – Antibiotic (Actinomycin)
• Dactinomycin: from Strep. parvilus,
tx of rhabdomyosarcoma and Wilm’s tumor in children, lifesaving tx for women with choriocarcinoma resistant to MTX
• MOA: binds non-covalently to double stranded DNA by partial intercalation between the adjacent G-C bases resulting to inhibition of DNA function.
Antineoplastic – Antibiotic (Anthracyclines) • With planar oxidized anthracene
nucleus fused to a cyclohexane ring connected via glycosidic bond with amino sugar
• MOA: association of the drug with DNA resulting from intercalation of the planar ring system reinforced by auxiliary binding of amino sugar.
Antineoplastic – Antibiotic (Anthracyclines)
• Daunorubicin: Inhibits
topoisomerase II. Isolated from Strep. peucetius useful for non-lymphocytic and lymphocytic leukemia.
• Doxorubicin: Inhibits topoisomerase II. Isolated from Strep. peucetius var. caesius doxorubicinol = cardiotoxic
Antineoplastic – Antibiotic (Anthracyclines) • Idarubicin: lacks 4-methoxy group
(increase inhibition of topoisomerase II) and terminal side chain; tx of blast phase chronic myelogenous carcinoma, less cardiotoxic than doxorubicin
• Epirubicin: 4’-epimer of doxorubicin (less cardotoxic) topoisomerase II inhibiotr
Antineoplastic – Antibiotic (Anthracyclines)
•Valrubicin: for BCG-refractory carcinoma of the urinary bladder
•Mitoxantrone: MOA: inhibits topoisomerase II and cause DNA strand breakage; can tint the urine blue.
Antineoplastic - Antibiotic •Bleomycin: a glycopeptide
antibiotic from Strep. verticillus, palliative treatment of squamous cell carcinoma, produce ROS causing single strand breakage. Lacks bone marrow toxicity
• SE: Pulmonary fibrosis
Antineoplastic - Antibiotic •Mitomycin C: “Bioreductive
alkylating agent”; from Strep. Caespitosus
•Plicamycin: first line for Paget’s
diease
Plant Products (Epipodophyllotoxin)
• From Mandrake/Mayapple • Inhibits microtubule function by acting on
topoisomerase II DNA strand breakage
• Etoposide: for testicular and small cell
lung cancer
• Teniposide: for acute lymphoblastic
leukemia (more potent inhibitor of topoisomerase II)
• inhibitors of topoisomerase I
• from Camptotheca acuminata
•Irinotecan: a semi-synthetic
analogue of camptotechin)
•Topotecan: Microscopic
hematuria can be seen
Plant Products (Camptothecins)
•Vinca alkaloids: usually obtained
from Vinca rosa/Catharantus roseus (Periwinkle); bind to tubulin disrupting formation and function of the mitotic spindle by arresting mitosis by inhibiting the polymerization of microtubules
Plant Products (Vinca alkaloids)
• Vincristine and vinblastine differ only in the group attached to the dihydroindole nitrogen, vincristine (formyl) and vinblastine (methyl).
Plant Products (Vinca alkaloids)
• Vinblastine: part of ABVD regimen for Hodgkin’s lymphoma. Extravasation is seen (most of the vincas) managed by the use of hyaluronic acid and heat.
• Vincristine: useful for Hodgkin’s lymphoma
• Vinorelbine: semi-synthetic for NSCLC
Plant Products (Vinca alkaloids)
• Taxanes: from Pacific Yew Tree (Taxus
brevifolia or T. baccatta). Administered with Cremophor EL and ethanol (due to poor water solubility)
• MOA is same with the vincas (binds to β-tubulin and cause cell death)
• Paclitaxel: highly protein bound, can
cause bradycardia. MOA: promotes assembly of microtubules
Plant Products (Taxanes)
•Docetaxel: promotes assembly of
microtubules; a semi-synthetic, SE includes reversible fluid retention
•Ixabepilone: semisynthetic amide
analog of epothilone B that is isolated from the myxobaterium Sorangium cellulosum
Plant Products (Taxanes)
Protein (Tyrosine) Kinase inhibitors
• is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that add a phosphate (PO4) group to a protein or other organic molecule. Phosphate groups can turn a protein off.
Protein (Tyrosine) Kinase inhibitors
• Erlotinib: inhibits epidermal growth factor receptor. SE: Acne. diarrhea
• Imatinib: inhibits BCR-ABL kinase and c-kit kinase
• Lapatinib: inhibits Her2/neu activity
• Sorafenib: inhibits intracellular and cell surface kinase like VEGFR
Protein (Tyrosine) Kinase inhibitors
• Sunitinib: inhibits receptor tyrosine kinases
• Dasatinib • Geftinib
Hormones
• Bicalutamide and Flutamide: androgen receptor antagonist used for tx of advance prostate cancer
• Fluvestrant: binds to estrogen
receptor used for the treatment of metastatic breast cancer
• Leuprolide acetate: inhibits
gonadotropin secretion for prostate cancer.
Hormones
• Megestrol acetate: advanced breast or endometrial cancer a progesterone antagonist
• Tamoxifen: Selective Estrogen Receptor Modulators (SERMs); an anti-estrogen and has triphenylethylene structurenon-steroidal agent for advanced breast cancer
Hormones
• Raloxifene: SERMs which is a benzothiophene derivative
• Goserelin: palliative treatment of advanced prostate carcinoma, breast cancer and endometriosis
• Mitotane: inoperable adrenal cortical carcinoma
• Dromostanolone: pallative treatment of metastatic breast cancer
Hormones
• Testolactone: palliative treatment of advanced or disseminated breast cancer
• Aminoglutethimide: treatment for Cushing’s syndrome
• Toremifene: for metastatic breast cancer
• Other agents includes: Nilutamide, Estramustine, Triptoralen
Hormones: Aromatase Inhibitors
• Blocks conversion of androgen to estrogen
• Exemestane: non-steroidal aromatase
inhibitor; for hormone dependent breast cancer
• Letrozole (non-steroidal aromatase
inhibitor) and anastrazole: for locally
advanced or metastatic breast carcinoma
Immunotherapy
• Interferon alfa – 2A: useful for patient 18 y/o or older for hairy cell leukemia and chronic myelogenous leukemia; has anti-proliferative effect
• Interferon alfa – 2B: indicated for hairy cell leukemia and treatment of malignant melanoma.
• Interferon alfa – n3
Immunotherapy
•Aldesleukin: stimulates T-cell
growth and regulation, proliferation and immunoglobulin production in B lymphocytes and macrophage activity enhancement
•Denileukin
•BCG
Monoclonal antibody “mab” • Product of rDNA techonology
•Alemtuzumab: Binds to B and T
cells
•Bevacizumab: Binds to vascular
endothelial growth factor
•Gentuzumab: Binds to CD33 on
leukemic cells
Monoclonal antibody “mab” • Ibritumomab tiutexan, Iodine -
131 tositumomab, Tositumomab: Binds to CD 20 on lymphoid cells
• Rituximab: a genetically engineered chimeric monoclonal antibody against CD20 antigen on malignant B lymphocyates
Monoclonal antibody “mab”
•Trastuzumab: for breast cancer
which selectively binds with high affinity to the extracllular domain of human epidermal growth factor 2 protein and neu receptor
Proteosome inhibitor
•Bortezomib
•Vorinostat
Miscellaneous
•Arsenic trioxide: tx of acute
promyelocytic leukemia
•Bexarotene: tx for cutaneous T-
cell lymphoma in patient refractory prior to systemic therapy
•Azathioprine: adjunct therapy to
prevent rejection of renal heterotransplants
Miscellaneous
•Asparaginase: enzyme from E.
coli. MOA: reduces asparagine in plasma making it unavailable for leukemic cells (Pegasparagase: modified L-asparaginase
Miscellaneous
• Sargamostim: a GM-CSF from Saccharomyces cerevisiae or E. coli. Use to promote bone marrow recovery in patient underwent autologus bone marrow transplantation
• Temsirolimus
Cytoprotectives • Counteract side effects of other
antineoplastic agents.
• Mesna: indicated for ifosfamide-induced
hemorrhagic cystitis
• Amifostine: reduce accumulative
toxicity from cisplatin and xerostoma
• Dexrazoxane: potent intracellular
chelating agent, reduce cumulative toxicity with doxorubicin
Matching Type
1. Terbinafine
2. Itraconazole
3. Caspofungin
4. Alendronate
5. Mycophenolate
A. Squalene monooxygenase
B. Sterol 14a-methylase
C. 1,3 β glucan synthase
D. Farnesyl diphosphate transferase
E. IMP dehydrogenase
Matching Type
1. Cilastatin
2. Oseltamivir
3. Atorvastatin
4. Etodolac
5. Entacapone
A. Viral neuraminidase
B. Renal dehydropeptidase
C. COMT
D. HMG CoA reductase
E. Prostaglandin endoperoxide synthase
Matching Type
1. Physostigmine
2. Sildenafil
3. EMB
4. Miglitol
5. Acarbose
A. α-amylase
B. α-glucosidase
C. Arabinosyl transferase
D. Phosphodiesterase inhibitor
E. Acetylcholinesterase inhibitor
Matching Type
1. Streptomycin
2. Chlortetracyline
3. Erythromycin
4. Gentamicin
5. Thienamycin
A. Streptomyces erythreus
B. Streptomyces cattleya
C. Micromonospora purpurea
D. Streptomyces griseus
E. Streptomyces aureofaciens
Matching Type
1. Vancomycin
2. Nystatin
3. Amphotericin B
4. Griseofulvin
5. Chloramphenicol
A. Streptomyces noursei
B. Streptomyces venezuelae
C. Penicillium griseofulvum
D. Streptomyces nodosus
E. Streptomyces orientalis
Matching Type
1. D-Cyloserine
2. Teicoplanin
3. Daptomycin
4. Quinupristin
5. Polymyxin B
A. Streptomyces pristinaespiralis
B. Streptomyces garyphalus
C. Actinoplanes teichomyceticus
D. Bacillus polymyxa
E. Streptomyces roseosporus
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