organic chemistry complete (pre-board review 2014)

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.

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.


Separation of Mixtures

Mixtures can be separated by physical means.

–Filtration

–Chromatography

–Distillation


Separation of Mixtures


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.


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


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.”


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


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)



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


Physical Properties of Drug Molecule

• Physical States: –Amorphous solid

–Crystalline solid

–Hygroscopic solid

–Liquid

–Gas


• 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


• Boiling point: temperature at

which the vapor pressure of the liquid is equal to the atmospheric pressure


• 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.


• Solubility: is the amount of a solute that can be dissolved in a specific solvent under given conditions.

–Solute

–Solvent

–Solvation/hydration


• Unsaturated solution

• Saturated solution

• Supersaturated solution

• Other definition of solubility: the maximum equilibrium amount of solute that can usually dissolve per amount of solvent


• 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


• 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


• 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.


SI Units

Temperature



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


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


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.


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


Precision and Accuracy



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.


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.


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


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


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


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.


•Neils Bohr


• 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.


• 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


•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.

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

The Periodic Table.ppt

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

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


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


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


Who discovered the structure of benzene?

Friedrich August Kekule

Phenol Ar-OH

Ether R-O-R

Aldehyde R- CHO

Ketone R-CO-R


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


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


Nitroso R-N = O

Nitrile (cyanide) R-C N

Imine

Imide


Diazo

Hydrazino R-NHNH2

Mercaptan (thiol) R-SH

Thioether R-S-R

Enol


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.


• Positional isomers ▫ Differ in the position of a non carbon

group.


• Functional Isomer ▫ Differ in the functional group.


•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.


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.


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.


• STEP 3: Substituent(s)/side chain(s) ▫ Identify the substituent(s) ▫ assigned the # of the C to which it is

attached

3 - methyl


• 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.


•Toxoid – a modified bacterial toxin

that has been made nontoxic but remains the ability to stimulate the formation of anti-toxin.


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.


• 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


•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.


•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.


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


• 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.


• 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


• 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


Helpful mnemonics

•Biotechnology techniques a. Recombinant DNA

b. Mutagenesis- site directed that fuse cell lines


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 _______.


• 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


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

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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 ____________.


•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.


•Termination of Drug Action

•Bioinactivation

•Detoxification

•Elimination


•Bioinactivation


•Detoxification


•Elimination


•Bioactivation

•Active Metabolites

•Prodrug

•Toxification


•Active Metabolites


•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.


•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


•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.


• 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


•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 ????


•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.


• 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.


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.


•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


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


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)


381

Geometric isomerism (cis-trans isomerism).


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.


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.


385

Bioisosteres are functional groups

which have similar spatial and

electronic character, but they retain

the activity of the parent.


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


• 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


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


•Novobiocin: topical use

• Mupirocin: topical use

• MOA: interference with RNA and protein synthesis

• Quinupristin/Dalfopristin (30:70)


• 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.


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


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


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


• 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


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


•Famciclovir: diacetyl prodrug of

penciclovir

•Penciclovir: tx of recurrent

Herpes labialis. used only topically whereas Famciclovir can be administered orally.


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


• Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ▫ Nevirapine ▫ Delaviridine ▫ Efavirenz: widely use NNRTIs

• Common side effect: RASHES


•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.


•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


• Vidarabine

• Clofarabine: Inhibits DNA synthesis

• Pentostatin: MOA: inhibition of adenosine deaminase increase dATP (cytotoxic to lymphocytes).

• Nelarabine and Pentostatin: inhibits DNA synthesis


• 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.


• 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.


•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.


• 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


• 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).


• 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


• 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.


• 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


• 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

organic chemistry complete (pre-board review 2014)

Self Improvement

properties of matter

volume properties of

physical means

composition of matter

extensive properties

o2 2h2o properties of

physical appearance

behavior of matter