PHARMACEUTICAL CHEMISTRY 2:

ORGANIC MEDICINAL CHEMISTRY

Example: The methane monooxygenase enzyme (MMO) is

capable of oxidizing methane and alkanes:
CH4 + O2 + NAD(P)H + H+ CH3OH + NAD(P)+ + H2O

Introduction to Medicinal Chemistry

Medicinal chemistry = interdisciplinary research area incorporating
different branches of chemistry and biology in the research for better and
new drugs (Drug Discovery).

The science, which deals with the discovery and design of new
and better therapeutic chemicals and development of these
chemicals into new medicines and drugs.

2. ALKENES
Also called olefins or unsaturated HCs, the alkenes have a
general formula of R-CH=CH2
are lipid soluble
The common reactions of alkenes are:

Through this we can:

Make new compounds
Determine their effect on biological processes.
Alter the structure of the compound for optimum effect and
minimum side effects.
Study uptake, distribution, metabolism and excretion of drugs.
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: materials obtained from both plant and
animal, e.g. vitamins, hormones, amino acids, antibiotics,
alkaloids, glycosides. etc.).
Synthesis compounds: either pure synthesis or synthesis
naturally occurring compounds (e.g. morphine, atropine,
steroids and cocaine) to reduce their cost.
Semi-synthesis compounds: Some compounds either can not
be purely synthesized or can not be isolated from natural
sources in low cost. Therefore, the natural intermediate of such
drugs could be used for the synthesis of a desired product (e.g.
semi synthetic penicillins).
Drugs can be classified according to their medicinal uses into two
main classes:
I-Pharmacodynamic agents: Drugs that act on the various
physiological functions of the body (e.g. general anaesthetic,
hypnotic and sedatives, analgesic etc.).
II-Chemotherapeutic agents: Those drugs which are used to
fight pathogens (e.g. sulphonamides, antibiotics, antimalarial
agents, antiviral, anticancer etc.).
Drugs can treat different types of diseases:
1. Infectious diseases: Born (transmitted) from person to
person by outside agents, bacteria (pneumonia, salmonella),
viruses (common cold, AIDS), fungi (thrush, athletes foot),
parasites (malaria)
2. Non-infectious diseases: disorders of the human body
caused by genetic malfunction, environmental factors, stress,
old age etc. (e.g. diabetes, heart disease, cancer. Haemophilia,
asthma, mental illness, stomach ulcers, arthritis).
3. Non-diseases: alleviation of pain (analgesic), prevention of
pregnancy (contraception) , anesthesia.
Review: Functional Groups
1. ALKANES
Also called paraffins or saturated HCs
have a general formula R-CH2-CH3 (R = a radical or a molecule
fragment) CnH2n+2
are lipid soluble
The common reactions of alkanes are:
- Halogenation
- Combustion

The common reactions of alkanes are:

halogenation
combustion

On the shelf, alkanes are chemically inert with

regards to light, air, heat, acids & bases.
In vivo, alkanes are stable; side-chain hydroxylation may occur.

On the shelf, volatile alkenes & peroxides may

explode in the presence of oxygen.
In vivo, alkenes are relatively stable, but these reactions may
occur:
- Hydration
- Epoxidation
- Peroxidation
- Reduction

3. AROMATIC HCs
Aromatic HCs are based on benzene ring. These molecules
exhibit multicenter bonding, which confers unique chemical
properties.
Aromatic HCs are lipid soluble.
The common reactions of a romatic HCs are:

On the shelf, aromatic HCs are quite stable.

In vivo, aromatic HCs undergo hydroxylation, epoxidation and
diol formation.

4.ALKYL HALIDES
Also known as halogenated HCs, the alkyl halides have a
general formula of R-CH2-X
Alkyl halides are lipid soluble.
Their solubility increases with the extent of halogenation.
The common reactions of alkyl halides are:
a.) nucleophilic substitution

The common reactions of phenols are reactions with strong

bases to form phenoxide ion, esterification with acids &
oxidation ( to form quinones, usually colored ).

b.) Dehalogenation

O
O
+

OH
O

In vivo, phenols undergo: sulfation, glucuronidation,

aromatic hydroxylation, & o-methylation.

On the shelf, alkyl halides are stable

In vivo, alkyl halides are not readily metabolized

5. ALCOHOLS
Alcohols contain a hydroxyl group (-OH) & may be classified
as primary, secondary or tertiary
a. Primary alcohols have a general formula of
R-CH2-OH
b. Secondary alcohols have a general formula of
R-CH-CH3OH
c. Tertiary alcohols have a general formula of
R2-C-OH
Low MW alcohols are water soluble; water solubility
decreases as HC chain length increases. Alcohols are
also lipid soluble.
The common reactions of alcohols:
a. Primary alcohols: are oxidized to aldehydes & then
carboxylic acids

7. ETHER
Have a general formula of ROR with an oxygen atom
bonded to 2 carbon atoms.
Low MW ethers are partially water soluble; water solubility
decreases with an increase in the HC portion of the molecule.
Ethers are also lipid soluble.
The common reactions of ethers is oxidation (to form
peroxides).
Note: On the shelf, peroxides may explode
In vivo, ethers undergo o-dealkylation. Stability
increases with the size of the alkyl group.
O
dealkylation
O CH3
OH + H C H
8. ALDEHYDES
Aldehydes have a general formula of R-CHO &
contain a carbonyl group ( C=O ).
Aldehydes are lipid soluble; low MW aldehydes are also water
soluble.
On the shelf, aldehydes oxidize to acids.
In vivo, aldehydes may also undergo oxidation to acids.
The common reactions of aldehydes are oxidation &
hemiacetal and acetal formation.

b. Secondary alcohols: are oxidized to ketones.

O
R

c.Tertiary alcohol: ordinarily are not oxidized.

On the shelf, alcohols are stable
In vivo, alcohols may undergo oxidation, glucuronidation
or sulfation.

Alcohol in the body

Once absorbed by the bloodstream, the alcohol leaves the body

in three ways:

The kidney eliminates 5 percent of alcohol in the urine.

The lungs exhale 5 percent of alcohol, which can be detected

by breathalyzer devices.

The liver chemically breaks down the remaining alcohol into

acetic acid.

As a rule of thumb, an average person can eliminate 0.5 oz (15

ml) of alcohol per hour. So, it would take approximately one
hour to eliminate the alcohol from a 12 oz (355 ml) can of beer.

The BAC increases when the body absorbs alcohol faster than
it can eliminate it. So, because the body can only eliminate
about one dose of alcohol per hour, drinking several drinks in
an hour will increase your BAC much more than having one
drink over a period of an hour or more.
6. PHENOLS
Phenols are aromatic compounds containing a hydroxyl group
(-OH)
a. Monophenols have one hydroxyl group
b. Catechols have two hydroxyl groups.
Phenols are lipid soluble; phenol itself is fairly water soluble.
Ring substitutions generally decrease water
solubility.
On the shelf, phenols are susceptible to air oxidation & to
oxidation on contact with ferric ions.

H + R'OH

O2 (air)
-H2O
+H2O

OR'
R

H + R'OH

OH
hemiacetal

OH
-H2O
+H

2O

OR'
R

OR'
acetal

9. KETONES
Have a general formula of RCOR &, like aldehydes, contain
a carbonyl grp
Ketones are lipid soluble. Low MW ketones are also water
soluble, with solubility decreasing as the HC portion of the
molecule increases.
Ketones are relatively non-reactive, although they may exist
in equilibrium with their enol forms
On the shelf, ketones are very stable.
In vivo, ketones may undergo some oxidation & some
reduction.
10. AMINES
Amines contain an amine group ( -NH2 )
a. Primary amines have a general formula of
R CH2-NH2
b. Secondary amines have a general formula of
R-CH2-NH-R
c. Tertiary amines have a general formula of
R-CH2-N-R2
d. Quarternary amines have a general formula of
R-CH2-N-R3
Low MW amines are water soluble; solubility decreases with
increased branching
Primary amines are more water soluble than secondary amines
Quaternary amines are quite water soluble, as are most amine
salts.
Amines are also lipid soluble
The common reactions of amines are oxidation & for alkyl
amines: salt formation with acids.
Aromatic amines which are less basic have less
tendency to react with acids.

On the shelf, phenolic amines are susceptible to air oxidation.

In vivo, amines may undergo minor glucuronidation,
sulfation, and methylation.
Primary amines
oxidative deamination
Primary & secondary amines acetylation.
Secondary & tertiary amines
N-dealkylation
Tertiary amines N oxidation.

The ability of a chemical compound to elicit a pharmacologic

or therapeutic effect is related to the influence of its various physical and
chemical (physicochemical) properties.
The most pharmacologically influential physicochemical
properties of organic medicinal agents (OMAs) are:
1.Solubility
2.Acidity and basicity
3.Reactivity
I. SOLUBILITY OF ORGANIC MEDICINAL AGENTS
Importance of solubility:
(1) Formulation of the drug in an appropriate dosage form; and
(2) Bio-disposition: Disposition of OMAs in the living system after
administration (absorption, distribution, metabolism, and excretion)
The solubility expression: in terms of its affinity/philicity or
repulsion/phobicity for either an aqueous (hydro) or lipid (lipo) solvent.
hydrophilic....................water loving
lipophobic.....................lipid hating
lipophilic.......................lipid loving
hydrophobic..................water hating

11. CARBOXYLIC ACIDS

Have a general formula of R-COOH & contain a
carboxyl group - COOH
Low MW carboxylic acids are water soluble, as are Na+ & K+
salts. Carboxylic acids are also lipid soluble.
On the shelf, carboxylic acids are very stable
The common rxns of carboxylic acids are: salt formation with
bases, esterification & decarboxylation.
O

R C OH

NaOH

R C O Na

ROH

R C OR

+ H2O

R C OH

Majority of organic medicinal agents possess balanced solubility

(have some degree of solubility in both aqueous and lipid media).
Why?????
Because there is a need for organic medicinal agents to move
through both aqueous (plasma, extracellular fluid, cytoplasm, etc.)
and lipid media (biologic membranes) in the biological system.
Solubility of OMAs should be viewed as being on a continuum between
high lipophilicity on one end of the spectrum and high hydrophilicity on
the other.
In order for a chemical compound to dissolve in a particular
solvent/medium the compound must establish attractive forces between
itself and molecules of the solvent.

+ H2O

In vivo, carboxylic acids undergo conjugation (with

glucuronic acid, glycine & glutamine) & oxidation

12. ESTERS
Have a general formula of R-COOR
Esters are lipid soluble; low MW esters are slightly water
soluble.
On the shelf, simple or low MW esters are susceptible to
hydrolysis, whereas complex, high MW or water insoluble
esters are resistant.
The common rxn of esters is hydrolysis.
On the shelf:
- simple or low MW esters are susceptible to hydrolysis
- complex, high MW or waterinsoluble esters are resistant
In vivo, esters undergo enzymatic hydrolysis.
13. AMIDES
Have a general formula of R-CO-NH2 or R-CONH-R (lactam
form)
Amides are lipid soluble; low MW amides are fairly water
soluble.
Amides have no common reactions
On the shelf, amides are very stable
Physico-chemical properties in relation to biological action
Drug action results from the interaction of drug molecules with either
normal or abnormal physiological processes.
Drugs normally interact with targets (which they are proteins,
enzymes, cell lipids, or pieces of DNA or RNA).

The most important intermolecular attractive forces (bonds) that are

involved in the solubilization process
Van der Waals Attraction
Dipole-Dipole Bonding
Ionic Bonding
Ion-Dipole Bonding
1. Van der Waals Attraction
weakest intermolecular force (0.5-1.0 kcal/mole)
electrostatic
occurs between nonpolar groups (e.g. HCs)
highly distance and temperature dependent
2. Dipole-Dipole Bonding
stronger (1.0 to 10 kcal/mole)
occurs electrostatically between electron deficient and electron
excessive /rich atoms (dipoles)
hydrogen bonding is a specific example of this bonding and
serves as a prime contributor to hydrophilicity
3.Ionic Bonding
electrostatic attraction between cations and anions
common in inorganic compounds and salts of organic
molecules
relatively strong (5 kcal/mole)
4.Ion-Dipole Bonding
electrostatic between a cation/anion and a dipole
relatively strong (1-5 kcal/mole)
low temperature and distance dependence
important attraction between organic medicinal agents and
H2O
Solubility Prediction
The relative solubility of an organic medicinal agent is a
function of the presence of both lipophilic and hydrophilic
features within its structure, which serve to determine the
extent of interaction of the OMA with lipid and/or aqueous
phases.
For example, the relative solubility of an organic medicinal
agent is the sum of the contributions of each group and
substituent to overall solubility.
Example:
Examination of the structure of chloramphenicol (indicates the
presence of both lipophilic (nonpolar) and hydrophilic (polar)
groups and substituents.

The presence of oxygen and nitrogen containing functional groups

usually enhances water solubility.
Lipid solubility is enhanced by nonionizable hydrocarbon chains and
ring systems.

Calculation steps of Log P for ORGANIC MEDICINAL AGENTS

1. The molecule is dissected into its various groups,
functionalities and substitutents
2. Appropriate hydrophilic/lipophilic fragment constants are
assigned and summed
3. 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).
II. Acidity and Basicity
Acidic and/or basic properties of OMAs are important in both:
1- Pharmaceutical phase (dosage formulation, etc.) and
2- Pharmacological phases (disposition, structure at target site, etc.).
The three aspects of acid-base chemistry:
(1) Definitions
(2) Recognition of acidic or basic organic functional groups and
(3) An estimation of the relative acid/base strength of these groups.
Definitions:
Acid: An organic compound containing a functional group that can
donate a proton (H+)
Base: An organic compound that contains a functional group that
can accept a H+
Recognition of acidic or basic organic functional groups
1- Common acidic organic functional groups
Carboxylic acid (-COOH)
Phenol (Ar-OH)
Sulfonamide (R-SO2NH2)
Imide (R-CO-NH-CO-R)
b-Carbonyl group (-CO-CHR-CO-)
2- Common basic organic functional groups
Aliphatic 1 (R-NH2), 2 (R2NH) and 3 (R3N)-amines
Heterocyclic amines
Aromatic amines (Ar-NH2)
Acidic and Basic Functional Group - Salt Formation
Salt: is the combination of an acid and a base
All salts are strong electrolytes (with few exceptions: mercuric and
cadmium halides and lead acetate)
The salt form of the drug is more soluble than its parent molecule
Drug salts can be divided into two classes:
1) Inorganic salts: are made by combining drug molecules with
inorganic acids and bases, such HCl, H2SO4, KOH and NaOH.
Inorganic salts are generally used to increase the aqueous
solubility of a compound
2) Organic salts: are made by combining two drug molecules,
one acidic and one basic. The salt formed by this combination
has increased lipid solubility and generally is used to make
depot injections (e.g. procaine penicillin).
III. Quantitative Structure Activity Relationship (QSAR)
As shown we can estimate the relative solubility of drugs on
the basis of the structure features.
However, there is a relationship between the quantity of the
drug that binds to the active site and its structure and thus, the
biological activity.
This relationship is called quantitative structure activity
relationship (QSAR).
Quantitative Structure Activity Relationship (QSAR)
QSAR can be used:
1- To predict the design of new compounds and
2- To reduce the types of chemical process involved in the biological
activity.
The biological activity of substances is related to oil water
distribution coefficient (distribution of the compound between the
aqueous and the lipid phases of the tissue), which is an important
parameter for solubility, thus the quantity of the drugs that binds to the
active site.
Structurally Non-Specific and Specific Activity
Drug activity can be classified as:

(a) Structurally non-specific or

(b) Structurally specific
1-Structurally non-specific activity is dependent on physical
properties like solubility, partition coefficients and vapor pressure and
not on the presence or absence of some chemical group.
Substances such as alkanes, alkenes, alkynes, alcohols, amides, ethers,
ketones and chlorinated hydrocarbons exhibit narcotic activity and
potency of each substance is related to its partition coefficient.
Structurally non-specific action results from accumulation of a drug in
some vital part of a cell with lipid characteristics.
The structurally non-specific drugs include general anaesthetics,
hypnotics together with a few bactericidal compounds and insecticides .
2-Structurally specific activity is dependent upon factors such as the
presence or absence of certain functional groups, intramolecular
distance, and shape of the molecules.
Activity is not easily co-related with any physical property and small
changes in structure often lead to changes in activity.
Structurally specific activity is dependent upon the interaction of the
drug with a cellular receptor.
Drug-receptor Interaction
Receptor is the site in the biological system where the drug exerts its
characteristic effects or where the drug acts. Receptors have an important
regulatory function in the target organ or tissue. Most drugs act by
combining with receptor in the biological system (specific drugs).
Example:
1. cholinergic drugs interacts with acetylcholine receptors.
2. synthetic corticosteroids bind to the same receptor as
cortisone and hydrocortisone
3. non steroidal anti inflammatory drugs inhibit
cyclooxygenase enzyme that will inhibit the formation of
prostaglandins which will lead to inflammation symptoms.
Note: Non-specific drugs do not act upon receptors.
The receptor substance is considered mostly to be a cellular constituent.
The ability of a drug to get bound to a receptor is termed as the affinity
of the drug for the receptor.
The receptors are also dynamic in nature and have a special chemical
affinity and structural requirements for the drug (specificity). Thus,
affinity represents kinetic constants that relate to the drug and the
receptor.
The drug elicits a pharmacological response after its interaction with the
receptor.
A given drug may act on more than one receptor differing both in
function and in binding characteristics (non-selective drugs).
There are also many factors effect changes in receptor concentration
and/or affinity.
A drug, which initiates a pharmacological action after combining with
the receptor, is termed agonist.
Drugs which binds to the receptors but are not capable of eliciting a
pharmacological response produce receptor blockage, these compounds
are termed antagonists.
Structural Features of Drugs and their Pharmacological Activity
Stereochemistry: Space arrangement of the atoms or three-dimensional
structure of the molecule. It plays a major role in the pharmacological
properties because:
Any change in the stereospecificity of the drug will affect its
pharmacological activity
The isomeric pairs have different physical properties (partition
coefficient, pka, etc.) and thus differ in pharmacological
activity.
The following steric factors influence pharmacological activity:
Optical and geometric isomerism
Conformational isomerism
Isosterism and bioisosterism
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.
Example:
The (+) or dextrorotatory isomer rotates light to the right
(clockwise). The (-) or levorotatory isomer rotates light to the left
(counterclockwise).
Enantiomers (optical isomers) can have large differences in potency,
receptor fit, biological activity, transport and metabolism.
Example:
Levo-phenol has narcotic, analgesic, and antitussive properties,
whereas its mirror image, dextro-phenol, has only antitussive activity.
Geometric isomerism (cis-trans isomerisms) occur as a result of
restricted rotation about a chemical bond, owing to double bonds or
rigid ring system in the molecule. They are not mirror images and have

different physicochemical properties and pharmacological activity

because different distances separate the functional groups of these
isomers. They generally do not fit to the same receptor equally well and
if these functional groups are pharmacophores (functional group
essential for binding) the isomers will differ in biologic activity.
Example:
cis-diethylstilbestrol has only 7% of the oestrogenic activity of
trans- diethylstilbestrol.

Conformational Isomerism and Pharmacological Activity

Conformational isomersim is the non-identical space arrangement of
atoms in a molecule, resulting from rotation about one or more single
bonds.
Almost every drug can exist in more than one
conformation and thus the drug might bind to more than one receptor but
a specific receptor site may bind only to one of many conformations of a
drug molecule.
Example:
The trans conformation of acetylcholine binds to the
muscarinic receptor, where as the gauche conformation binds to the
nicotinic receptor.
Isosterism, Bioisosterism and Pharmacological Activity
Isosterism: Any two ions or molecules having an identical number and
arrangement of electrons
(e.g. CO2 and NO2)
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. Bioisosteres are functional groups which have
similar spatial and electronic character, but they retain the activity of the
parent.
Bioisosteres

chemical substituents or groups with similar physical or

chemical properties which produce broadly similar biological
properties to another chemical compound. In drug design, the
purpose of exchanging one bioisostere for another is to enhance
the desired biological or physical properties of a compound
without making significant changes in chemical structure.

Bioisosterism is important in medicinal chemistry because:

1. Maintain similar biological properties.
2. Resolved biological problems effectively (potency, side
effects, separate biologic activities and duration of action)
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.
Classical and Non-Classical Bioisosteres:
Classical bioisosterism was originally formulated as a response to the
observation that different atoms with the same valence electron structure
had similar biological properties.
For example, the replacement of a hydrogen atom with a fluorine atom at
a site of metabolic oxidation in a drug candidate may prevent such
metabolism from taking place. Because the fluorine atom is similar in
size to the hydrogen atom the overall topology of the molecule is not
significantly affected, leaving the desired biological activity unaffected.
However, with a blocked pathway for metabolism, the drug candidate
may have a longer half-life.
Classical and Non-Classical Bioisosteres:
Nonclassical bioisosteres may substitute a linear functional group for a
cyclic moiety, an alkyl group for a complex heteroatom moiety, or other
changes that go far beyond a simple atom-for-atom switch.
For example, a chlorine -Cl group may often be replaced by a
trifluoromethyl -CF3 group, or by a cyano -CN group. Another example
is aromatic rings, a phenyl -C6H5 ring can often be replaced by a
different aromatic ring such as thiophene or naphthalene which may
improve efficacy, change specificity of binding, or reduce metabolically
labile sites on the molecule, resulting in better pharmacokinetic
properties.
PROCESS OF DRUG DEVELOPMENT
1. Target Identification
1.1. Area of interest in terms of drug indication
Example: Oral hypoglycemic, diuretics, anti-cancer
potential, etc.
1.2. Relevant cellular or molecular targets
1.3. Appropriate assay established or to be developed
1.4. Available relevant literature
1.5. Patent situation in the target area

2. Identification of Resources
2.1. Potential resources for novel drugs
2.1.1. Natural organisms (plant, fungi, animals)
2.1.2. Combinatorial chemistry - technique in which
molecular constructions can be synthesized and tested for
biologic activity.
2.1.3. Structure-based drug design
3. Methods for Drug Discovery
3.1. High throughput screening of random samples (HTS):
Including screen development, primary and secondary screening
3.2. Ethnobiological approach: Traditional use of natural
organisms for
medicines
- how plants are used and perceived across human societies.
3.2.1. Systematic screening of:
3.2.1.1. Published literature on traditional medicinal plant use
(e.g. documented traditional healers experience)
3.2.1.2. Historical texts (e.g. ancient botanico-medicinal
profile)
Advantages:
- Pre-selection of potentially active resources
- Promising safety profile (age-long experience)
- Cost-efficient and comparatively fast
4. Selection of Samples
4.1. Continuous availability
4.2. Quality variations
4.3. Sustainable cultivation / harvesting
4.4. Biodiversity regulations
4.5. Existing patent and intellectual property rights
5. Phytopharmacy

2 Standard Analytical Methods in Phytopharmacy:

a. TLC - Thin Layer Chromatography
b. HPLC
- High Performance Liquid Chromatography
6. Preclinical Studies
6.1. Synthesis and purification of the new drug
6.2. Pharmacology of the new drug:
6.2.1. Pharmacokinetics: absorption, distribution, metabolism,
excretion, half-life
6.2.2. Pharmacodynamics: mechanism of action and estimates
of therapeutic effects
6.2.3. Toxicology including carcinogenicity, mutagenicity, and
teratogenicity
6.3. Efficacy studies on animals
7. Investigational New Drug (IND)
7.1. Investigational New Drug (IND): Application for
permission to administer a new drug to humans
7.2. Outlines the proposal to use the new drug for human
testing in clinical trials
7.3. Studies in humans can only begin after IND is reviewed
and approved by the FDA and an institutional review board (IRB).
8. Clinical studies
8.1. Phase 1: Efficacy studies on healthy volunteers
8.2. Phase 2: Clinical studies on a limited scale
8.3. Phase 3: Comparative studies on large number of
patients
8.4. New Drug Application (NDA): Regulatory
review
8.5. Phase 4: Continued comparative studies.
Registration and market introduction
Phase I
Typically involves 20-80 healthy volunteers (no women of
childbearing potential)
Emphasis is on drug safety

Goal is to identify major side effects, metabolism and routes of

excretion
Lasts about 1 year

Phase II
Typically involves 100-300 individuals who have the target
disease
Emphasis is on effectiveness
Patients receiving the drug are compared to similar patients
receiving a placebo or another drug
Lasts about 2 years

Phase III
Typically involves 1000-3000 patients
Emphasis is on safety and effectiveness
Investigates through well-controlled studies different
populations and different dosages as well as uses new drug in
combination with other drugs
Lasts about 3 years
NDA

Pre-NDA period: FDA and drug sponsors meet

Submission of NDA: Formal step asking the FDA to consider
approving a drug for marketing
FDA has 60 days to decide whether it will file it for approval
consideration
If filed, a review team is assigned to evaluate the new drug
Phase IV
Post-market surveillance of the drug to continually assess the
safety of the drug
Pharmacovigilance
May include incidence and severity of rare adverse reactions,
cost-effectiveness analyses, comparative trials, and quality of
life studies
Phase V
refer to comparative effectiveness research and communitybased research
it is used to signify the integration of a new clinical treatment
into widespread public health practice
9. Future Researches:
9.1. Priority areas
9.2. improve safety and efficacy records
9.3. reduce animal utilization (cell lines; early human
volunteers, )
9.4. new diseases
9.5. new biology - (clone human receptors; disease
model by gene changes)
9.6. Patent and increasing cost
Metabolic Changes of Drugs and Related Organic Compounds
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
Two categories:

Catabolism breaks down organic matter

Anabolism uses energy to build up or construct components of

cells such as proteins and nucleic acids.
Drug Metabolism
also called biotransformation
biochemical changes that drugs and xenobiotics (foreign
chemicals) undergo in the body leading to formation of
different metabolites with different effects
xenobiotics undergo variety of biotransformation pathways to
produce intermediate metabolites and excreted products,
including unchanged parent drug

Metabolism plays a central role in the formation of:

1. Inactive metabolite
their pharmacologically active parent compounds become
inactivated or detoxicated
Hydrolysis of procaine to p-aminobenzoic acid and
diethylamine results in loss of anesthetic activity
Oxidation of 6-mercaptopurine to 6-mercaptopuric acid
results in loss of anticancer activity
2. Metabolites that retain similar activity
retain the pharmacologic activity of their parent compounds to
a greater or lesser degree
Imipramine is demethylated to the essentially equiactive
antidepressant, desipramine.
Acetohexamide is reduced to the more active hypoglycemic,
1-hydroxyhexamide.
Codeine is demethylated to the more active analgesic,
morphine.
3. Metabolites with altered activity
develop activity different form that of their parent compound
Antidepressant iproniazid is dealkylated to the antitubercular,
isoniazid.
Vitamin retinoic acid (vit, A) is isomerized to the anti-acne
agent, isoretinoic acid.
4. Bioactivated metabolites
pharmacologically inactive parent compounds are converted to
active species within the body.
These parent compound are known as PRODRUGS
Prodrug enalapril is hydrolyzed to enalaprilat, a potent
antihypertensive (ACE inhibitor).
Prodrug sulindac (NSAID), a sulfoxide, is reduced to the active
sulfide.
Antiparkinsonian levodopa is decarboxylated in the neuron to
active dopamine.

General Pathway of Drug Metabolism

1. Phase I or Functionalization (Non-synthetic reactions)
Reactions includes:
1.1. Oxidative Reaction
1.2. Reductive Reaction
1.3. Hydrolytic Biotransformation


I.

polar functional groups are introduced into the molecule or

unmasked by oxidation, reduction, or hydrolysis
Oxidation
majority occurs in the liver
metabolic sites are the extrahepatic tissues (intestinal
mucosa, liver,& kidney)
catalyzed by cytochrome P450 (CYP450) bound to
smooth ER of the liver and require both NADPH and a
porphyrin prosthetic group
CYP450 exists in multiple isoforms or families
6 mammalian families are involved in the steroid and bile
acid metabolism: CYP7, CYP11, CYP17, CYP21, CYP27
4 mammalian families are involved in xenobiotic, or drug,
metabolism: CYP1, CYP2, CYP3, CYP4
CYP450 and microsomal oxidases catalyze aromatic,
alipathic, olefinic, benzylic, allylic, and a-hydroxyaltions;
N-, O-, and S-dealkyaltions, oxidative deamination, N- and
S-oxidations; desulfuration; dehalogenation; and
oxidations of alcohols and aldehyde.
Increased polarity of the oxidized products enhances
water solubility and reduces their tubular reabsorption
favoring their excretion in the urine; these metabolites are
more polar than their parent compound and undergo
further biotransformation by phase II pathways.

Role of Cytochrome P-450 Monooxygenases in Oxidative

Biotransformation:
General Equation describing the oxidation of many xenobiotics (R-H)
forming a metabolite (R-OH).

Mixed Function in the biotransformation with

Monooxygenases
Requires both molecular and a reducing agent
Enzyme responsible for transferring an Oxygen atom to the
substrate is called Cytochrome P-450
Cytochrome P450 structure:
Important features:
Plays a vital role in oxidation of lipophilic xenobiotics
metabolize almost unlimited number of diverse substrates by a
variety of oxidative transformations.
located in the endoplasmic reticulum

II. Reduction
to create more polar functional groups that can be eliminated in
the urine
CYP450 system might be involved in some reductions
bacteria in the GIT are involved in the azo and nitro
reductions
III. Enzymatic hydrolysis

addition of water across a bond results in a more polar

metabolites
a. Esterase enzymes
nonspecific and catalyze de-esterification, hydrolyzing
nonpolar to 2 polar, more water soluble compounds: alcohol and acid;
prodrugs into active forms
b. Amidase enzymes
amides into amines and acids (deamination), occurs in the liver
2. Phase II or Conjugation Reaction (Non-synthetic Reactions)
2.1. Glucoronic Acid Conjugation
2.2. Sulfate Conjugation

2.3. Conjugation with Glycine, Glutamine and other Amino

Acids
2.4. Glutathione or Mercapturic Acid Conjugation
2.5. Acetylation
2.6. Methylation
functional groups of the original drug or the metabolite
a phase I reaction are masked by a conjugation reaction
most conjugates are very polar resulting in rapid drug
elimination
Conjugation reactions
combine the parent drug (or its metabolites) with certain
endogenous constituents:
glucuronic acid, glycine, glutamine, sulfate, glutathione,
two-carbon acetyl fragment, or one-carbon methyl fragment
require both high-energy molecule (coenzyme bound to
endogenous substrate, parent drug or phase I metabolite)
and an enzyme (transferases).
conjugates are highly polar and unable to cross cell
membrane, making them always pharmacologically
inactive and of little or no toxicity.
Factors Influencing Drug Metabolism:
1. Chemical Structure
- the presence or absence of functional groups determine
the necessity, route, and extent of metabolism
2. Species Difference
- Qualitative differences result from a genetic deficiency of a
particular enzyme or a difference in particular endogenous substrate;
occur primarily with phase II reactions
- Quantitative differences result from difference in enzyme
level, presence of species specific isozymes, a difference in the amount
of endogenous inhibitor or the inducer, or difference in the extent of
competing reactions; phase I reactions.
3. Physiologic or Disease State
- Pathologic factors that alter liver function can affect a
drugs hepatic
clearance
- Congestive heart failure decrease hepatic blood flow by
reducing cardiac output which alters the extent or drug metabolism.
- Alteration in albumin production decrease in plasma
albumin can increase the fraction of unbound (free) drug to exert a more
intense pharmacologic activity
4. Genetic Variation
- Acetylation rate depends on the amount of N-acetyltansferase present
Fast acetylators are more prone to hepatoxicity from the
antitubercular agent isoniazid than slow acetylators, whereas slow
acetyaltors are more prone to isoniazids other toxic effects.
5. Drug Dosage
Increase in drug dosage results in increased drug concentrations
and can saturate metabolic enzymes. If it exceeds 50% saturation, it
follows mix of zero- and first-order kinetics. At 100% saturation,
metabolism follows zero-order kinetics.
When the metabolic pathway is saturated, an alternative
pathway may be pursued which can lead to hepatotoxicity.
6. Nutritional Status
- Low protein diet lead to deficiency of certain amino acids,
also
decrease oxidative drug metabolism capacity.
- Deficient in essential fatty acids decrease synthesis of
certain
drug-metabolizing enzyme, thus reduce the
metabolism of ethyl-morphine and hexobarbital.
- Deficiency of certain dietary minerals:
Mg, Ca, Zn deficiency decrease drug-metabolizing
capacity
Fe deficiency increase drug-metabolizing capacity.
- Deficiencies of vitamins
Vit. C deficiency decrease in oxidative pathways
Vit. E deficiency retard dealkylation and
hydroxylation
7. Age
- Metabolizing enzyme systems are not fully developed at birth,
thus infants and young children need to receive smaller doses of drugs
than adults to avoid toxic side effects.
- In older children, drugs may be less active than adults, if
dosage is based on weight.
- In elderly, metabolizing enzymes system decline, thus slows
the rate of drug elimination, causing higher plasma drug level per dose
than in young adults.
8. Gender
- Metabolism of diazepam, caffeine, acetaminophen is slightly
faster in women.

- Oxidative metabolism of propranolol, chlordiazepoxide,

lidocaine, and some steroids occurs faster in men.
9. Circadian rhythms
The nocturnal plasma levels of drugs, such as theophylline and
diazepam, are lower than diurnal plasma levels.
10. Drug Administration Route
- Oral administration. The drug is absorbed from the GIT and
transported to the liver through the hepatic portal vein before entering
the systematic circulation (first-pass effect, or presystematic
elimination). Thus, the drug is subject to hepatic metabolism before it
reaches the site of action
- Intravenous administration. The drug is delivered directly
to the bloodstream without being metabolized in the liver. Intravenous
doses undergoing first-pass effect are much smaller than oral doses.
- Sublingual administration and rectal administration also
bypass first-pass effects.
Extrahepatic Metabolism
A. Drug biotransformation that takes place in tissues other than the
liver.
Sites:
portal of entry GI mucosa, nasal passages, and lungs
portals of excretions kidneys

B. Metabolism sites
1. Plasma contains esterases which are responsible for hydrolysis of
esters
2. Intestinal mucosal enzyme important for drug undergoing microsomal
oxidation, glucuronide conjugation, and sulfate conjugation.
Lipid-soluble drug that passes through the intestinal mucosa is
metabolized into polar or inactive metabolites before entering the blood.
3. Intestinal bacterial flora secretes enzymes capable of metabolizing
drugs and other xenobiotics. Factors (age, diet, disease state, and
exposure to environmental chemicals or drugs) that modifies the
intestinal flora may modify drug activity.
4. Acidic environment of the stomach produces enzymatic degradation of
pen G, carbenicillin, erythromycin, tetracycline, proteins and peptides.
5. Nasal mucosa provides a high level of CYP450 activity which alter
the amount of drug that reaches the systemic circulation.
6. Lung is responsible for the first-pass metabolism of drugs
administered intravenously, intramuscularly, transdermally, or
subcutaneously. The lung provide second-pass metabolism for drugs
leaving the liver.
C. Placental and Fetal Metabolism
If a drug or other xenobiotic is lipid soluble also pass through
the placenta. Drugs in their active form in the maternal circulation pass
unchanged into the fetal circulation.
Strategies to Manage drug Metabolism
- decreasing the overall extent of metabolism and increasing the duration
of action.

A. Pharmaceutical strategies
- involve the use of different dosage forms to either avoid or
compensate for rapid metabolism.

1. Sublingual tablets directly into the systemic circulation and

bypassing hepatic first-pass metabolism. Nitroglycerin, a rapidly acting
antianginal agent, if given sublingually.
2. Transdermal patches and ointment formulations provide a
continuous supply of drug over an extended period of time.
3. Intramuscular depot injections provide a continuous supply of drug
over an extended period of time.
Hydrolysis of estradiol and testosterone produces a steady
supply of these rapidly metabolized hormone.
4. Enteric-coated formulations can protect acid sensitive drugs as they
pass through the acidic environment of the stomach. e.g. methenamine,
erythromycin, omeprazole.
5. Nasal administration delivery of peptides (calcitonin salmon)
which have very low oral bioavailability. Aerosolized drugs penetrate a
thin epithelial layer to reach abundant capillary beds. Lungs contain
protease inhibitor which allows greater stability of the peptides.
B. Pharmacologic strategies
- concurrent use of enzyme inhibitor to decrease drug
metabolism.
- concurrent use of an additional agent prevents the toxicity
caused by metabolites.
Example:
Levodopa (L-dopa)
- amino acid precursor of dopamine,
- treatment of parkinsonism
- penetrate blood-brain barrier and reach CNS; in brain it is
decarboxylated to dopamine
(a) to assure the adequate concentrations of L-dopa reach the
CNS, peripheral metabolism of the drug must be blocked
(b) concurrent administration of carbidopa cannot penetrate
the BBB, prevents the peripheral formation of dopamine.
b-Lactam antibiotics
- antibacterial activity is reduced by microorganisms capable of
secreting b-lactamase which hydrolyzes the b-lactam ring and inactivates
the antibiotic.
(a) b-lactamase inhibitor (clavulinic acid) is used in
conjunction with a penicillin (amoxicillin) to treat infections
Enzymes Catalyzing Phase I Metabolism
cytochrome P-450
aldehyde and alcohol dehydrogenase
deaminases
Esterases
Amidases
epoxide hydratases
Enzymes Catalyzing Phase II Metabolism
glucuronyl transferase (glucuronide conjugation)
sulfotransferase (sulfate conjugation)
transacylases (amino acid conjugation)
acetylases
Ethylases
Methylases
glutathione transferase