Principles of Organic Medicinal

Chemistry
MARY DAWN A. LEGASPI

Medicinal chemistry

defined by IUPAC specified commission as it

concerns the discovery, the development, the
identification and the interpretation of the mode of
action of biologically active compounds at the
molecular level

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Medicinal chemistry

the subject explains the design and production of

compounds that can be used for the prevention,
treatment or cure of human and animal diseases
it includes the study of already existing drugs, of their
biological properties and their structure-activity
relationships
is the application of chemical research techniques to
the synthesis of pharmaceuticals
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Medicinal chemistry covers the

following stages:
I.

In the first stage new active substances or drugs are

identified and prepared from natural sources, organic
chemical reactions or biotechnological processes. They
are known as lead molecules.
II. The second stage is optimization of lead structure to
improve potency, selectivity and to reduce toxicity.
III. Third stage is development stage, which involves
optimization of synthetic route for bulk production and
modification of pharmacokinetic and pharmaceutical
properties of active substance to render it clinically
useful.
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General Principles of Drug Action

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DRUGS
medicinal agents used for diagnosis, prevention,
treatment of symptoms, and cure of diseases
Contraceptives would be outside of this definition unless
pregnancy was considered a disease.
All drugs have the potential for producing more than one
response.
Some adverse drug responses which are unavoidable are
appearing at therapeutic doses are termed as side effects.
In contrast, adverse drug effects appearing at extreme
drug doses are described as toxic effects.
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CLASSIFICATION OF DRUGS

1.
2.
3.
4.
5.

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By originsources of drugs
By Action
By therapeutic use
By site of drug action
By Chemical Structure

CLASSIFICATION OF DRUGS:
By originsources of drugs
A. Synthetic
B. Natural
A.
B.
C.
D.

Plants
Animals
Microorganisms
Minerals

C. Semi-synthetic
D. Biosynthetic
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Synthetic
chemically pure
Most widely used
Advantages:

Inexpensiveness
ease of quality control
mass production
therapeutic efficacy

Example: Chloroquine, acetylsalicylic acid,

chlorpromazine, ephedrine, paracetamol
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Natural: Plants

A number of plant based drugs such as vincristine,

taxol, digoxin, quinine, reserpine, ergotamine,
ephedrine, colchicine etc. are still a part of standard
therapy.
Most of these dont have any synthetic substitutes.
Several other plant products are used in formulations
that are sold across the counter in several countries

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Natural: Animals

Some modern drugs continue to be derived from

animal sources because the synthesis of such
chemicals is very cumbersome and expensive.
Ex. : Gonadotrophins, heparin, insulin, thyroid
extracts and enzymes

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Natural: Microorganisms
Following the accidental discovery of penicillin from a
mould in 1928 and its successful use in chemotherapy
in 1940, a large number of antibiotics have been
discovered from a variety of soil fungi and some
bacteria.
These drugs formthe most important group of
chemotherapeutic agents used against infective
diseases.
Ex. : Penicillin, Streptomycin, Tetracycline
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Natural: Minerals

Minerals or mineral-containing medicated springs

have been in use since time immemorial.
Minerals of medicinal value are iron, calcium,
magnesium, aluminium, sodium, potassium etc.

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Semi-synthetic
In some cases, especially with complex molecules, the
synthesis of a drug may be very difficult or expensive
and uneconomical. At the same time, the ones
derived from natural sources may be impure. In these
cases semisynthetic processes are used
Ex. : 6-Aminopenicillanic acid is obtained from the
fungus Penicillium chrysogenum.

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Biosynthetic
Several drugs are complex polypeptides. It is difficult
to obtain these drugs in pure form from natural
sources and are very expensive to synthesize in the
laboratory.
Ex: Biosynthetic human insulin, interferon,
erythropoietin, hepatitis vaccine

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CLASSIFICATION OF DRUGS:
By Action
According to similarity of drug effects: Ex: marijuana
and atropine both increase heart rate and cause
dryness of the mouth. Thus, marijuana would be
classified as atropine-like drug.

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CLASSIFICATION OF DRUGS:
By therapeutic use
These drugs mainly affect the normal dynamic processes of the
body. They are;
i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
x.
xi.
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Anti-arrhythmics
Antianginals
Vasodialators
Anti-hypertensives
Cardiotonics
Hypocholesteric agents
Antiallergic agents
Drugs acting on GIT
Drugs influence renal function
Drugs acting on central nervous system
Drugs acting on peripheral nervous system
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CLASSIFICATION OF DRUGS:
By site of drug action
Ex: Alcohol is a depressant drug because of its
depresant CNS action. This system is limited when a
drug has an effect at several body sites (e.g., the CNS
stimulant cocaine also has local anesthetic (pain
reducing) effects

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CLASSIFICATION OF DRUGS:
By Chemical Structure
Drugs are classified according to the chemical moiety or
functional group. They may be further subclassified as:
i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
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Hydrocarbons
Halogenated compounds
Alcohols
Carboxylic acids
Phenols
Nitro compounds
Amides
Amines
Sulphonamides, sulphones, stilbenes, thioureas, ureides etc.
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Characteristics of Different Route of

Administration
1. Oral route
A. Swallowed
B. Sublingual

2.
3.
4.
5.
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Rectal route
Epithelial route
Inhalation route
Parenteral route
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Characteristics of
Oral route: swallowed
Most drugs in this route of administration are absorbed in
small intestine.
Full stomach delays absorption (e.g. alcohol).
Several drugs may subject to first-pass metabolism by liver
(Ex: Aldosterone, corttsol, acetyl salicylic acid).
The drug candidates may undergo extensive metabolism
before reaching target receptors.
It is safer, more convenient, noninvasive, often painless,
the medicament need not be sterile and so cheaper.
Both solid dosage forms and liquid dosage forms can be
given orally
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Characteristics of
Oral route: Sublingual
The tablet or pellet containing the drug is placed
under the tongue or crushed in the mouth and spread
over the buccal mucosa.
In this mode of administration fast systemic
absorption is observed which, bypass
gastrointestinaltract entry.
It avoids absorption and first-pass metabolism in the
liver and is useful for those likely to vomit from
swallowed medication.
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Characteristics of
Rectal route
the drugs are absorbed directly from the rectum.
It partially avoids first-pass metabolism by liver and also for
those likely to vomit and lose swallowed medication.
Certain irritant and unpleasant drugs can be put into
rectum as suppositories or retention enema for systemic
effect.
Ex: Aminophylline, indomethacin, paraldehyde, diazepam,
ergotamine, and few other drugs are some times given
rectally
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Characteristics of
Epithelial route
In this technique drugs are absorbed through the
skin.
This route is useful for those likely to vomit (e.g.
nicotine patch).
Highly lipid soluble drugs can be applied over the skin
for slow and prolonged absorption.
The drug bypasses the liver by this route of
administration.
The drug can be incorporated in an ointment and
applied over specified area of skin.
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Characteristics of
Inhalational route
Volatile oils and gases are given by inhalation ex:
general anesthetic, amylnitrite.
The drugs enter the bloodstream very rapidly from
the lungs.
no absorption or first-pass metabolism problems
occur.
This route is potentially dangerous because it is so
fast and direct
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Characteristics of
Parenteral route
Parenteral administration refers to administration by
injection into tissue fluid or blood without having to cross
the intestinal mucosa.
This route can be employed even in unconscious,
uncooperative or vomiting patient.
The important parenteral routes are subcutaneous (SC);
intramuscular (IM); intravenous (IV).
The rate of absorption depends on blood flow through
injection site. SC or IM exert effects more quickly than oral
administration.
IV is the fastest route and most certain in terms of
obtaining desired concentration of drug in blood plasma
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SITES OF Drug Action

1. Enzyme inhibition
2. Drug-Receptor interaction
3. Non-specific interactions

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Enzyme inhibition
Drugs act within the cell by modifying normal
biochemical reactions.
Enzyme inhibition may be reversible or nonreversible; competitive or non-competitive.
Antimetabolites may be used which mimic natural
metabolites

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Drug-Receptor interaction
Drugs act on the cell membrane by physical and/or
chemical interactions.
This is usually through specific drug receptor sites known
to be located in the membrane.
A receptor is the specific chemical constituents of the cell
with which a drug interacts to produce its pharmacological
effects.
Some receptor sites have been identified with specific
parts of proteins and nucleic acids.
In most cases, the chemical nature of the receptor site
remains obscure
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Non-specific interactions

Drugs act exclusively by physical means outside of

cells.
These sites include external surfaces of skin and
gastrointestinal tract.
Drugs also act outside of cell membranes by chemical
interactions.
Neutralization of stomach acid by antacids is a good
example
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DRUGS:
Action VS Effects
Actions of drugs are the biochemicals, physiological
mechanisms by which the chemical produces a
response in living organisms.
The effect is the observable consequence of a drug
action.
For example, the action of penicillin is to interfere
with cell wall synthesis in bacteria and the effect is
the death of bacteria.
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MODE OF DRUG ACTION

the site of action and the general nature of the drugcell interaction
1.
2.
3.
4.

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Killing foreign organisms

Stimulation and depression
Irritation
Replacement

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MODE OF DRUG ACTION:

Killing foreign organisms
Chemotherapeutic agents act by killing or weakening
foreign organisms such as bacteria, worms, and
viruses.
The main principle of action is selective toxicity, i.e.
the drug must be more toxic to the parasite than to
the host.

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MODE OF DRUG ACTION:

Stimulation and depression
Drugs act by stimulating or depressing normal
physiological functions.
Stimulation increases the rate of activity while
depression reduces it

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MODE OF DRUG ACTION:

Irritation
It is a non-specific action of a drug that can occur in all
the body tissues.
Certain drugs act by causing irritation.
Ex: Drugs like senna and castor oil show their laxative
effects by their irritant action on gastrointestinal tract

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MODE OF DRUG ACTION:

Replacement
Drugs serve as replacement of essential body
chemicals that are either absent or present in less
than required quantity due to disease.
Ex:
Insulin is used in diabetes.
Levodopa therapy in Parkinsons disease

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MECHANISM OF DRUG ACTION

1.
2.
3.
4.

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PHYSICAL PROPERTIES
CHEMICAL PROPERTIES
THROUGH ENZYMES
THROUGH RECEPTORS

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MECHANISM OF DRUG ACTION:

Physical Properties
A physical property of the drug is responsible for its action.
i.
ii.
iii.
iv.

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Taste. Bitter taste drugs increase the flow the hydrochloric

acid reflexly in the stomach. Ex: Cloxacillin
Mass. By increasing the bulk of drug in intestine produce
laxative effect.
Adsorption. Certain drugs like kaolin adsorb water on to its
surface and there by reduce gastric motility
Radioactivity. The radioactive substances are commonly
used to treat cancer.

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MECHANISM OF DRUG ACTION:

Chemical Properties
The drugs react extracellularly according to simple
chemical reactions like neutralization, chelation,
oxidation etc. Ex:
i.
ii.

Aluminium hydroxide neutralizes acid in stomach

Toxic heavy metals can be eliminated by chelating
agents like EDTA, BAL, penicillamine etc.
iii. Oxidising agents are germicidal.

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MECHANISM OF DRUG ACTION:

Through Enzymes
Enzymes are very important targets of drug action because
almost all biological reactions are carried out under the
influence of enzymes.
Drugs may either increase or decrease enzymatic
reactions. Ex
i.
ii.
iii.
iv.
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Adrenaline stimulates adenyl cyclase

Pyridoxine acts as a cofactor and increases decarboxylase
activity
Allopurinol competes with hypoxanthine for xanthine
oxidase
Physostigmine and neostigmine compete with
acetylcholine for cholinesterase.
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MECHANISM OF DRUG ACTION:

Through Receptors
A large number of drugs act through specific
macromolecular components of the cell, which
regulate critical functions like enzymatic activity,
permeability, structural features, template function
etc.
These macromolecules, which bind and interact with
the drugs, are called receptors

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DRUG RECEPTOR INTERACTION

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RECEPTOR
is a component of a cell or organism that interacts
with a drug and initiates the chain of biochemical
events leading to the drugs observed effects

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Drug-Receptor Complex
Nomenclature
1. Agonist
2. Antagonist

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AGONIST
A drug that activates a receptor is knows as agonist, which
has following properties;
Agonists can differ in both affinity and efficacy for the
receptor
High efficacy agonists are full agonists because they elicit
maximal effects
Low efficacy agonists are partial agonists because they
cannot elicit a maximal effect at receptors even at high
concentrations (false transmitters)
Direct agonists act on receptors, while indirect agonists
facilitate the actions of the endogenous agonist (the
neurotransmitter, itself)
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ANTAGONIST
A drug that does not activate the receptor is antagonist,
which possess the following features;
Antagonists also prevent the activation of the receptor by an
agonist, thus antagonists are essentially zero efficacy drugs
Competitive antagonists bind to the same binding site as the
agonist and therefore compete with the agonist for that
binding site
Non-competitive antagonists have a different binding site to
the agonist and therefore do not compete with the agonist.
Some non-competitive antagonists have a binding site within
the ion channel associated with the receptor complex.
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Chemical Nature of Receptors

Most of the receptors like regulatory enzymes
(dihydrofolate reductase enzyme)
acetylcholinesterase transport proteins and structural
proteins (Tubulin) are protein in nature and some are
glycoproteins (G-protein coupled receptors) or
nucleic acids.

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Types of Receptors

I. Ligand-gated ion channels

II. G-protein (Guanine nucleotide-regulatory protein)
coupled receptors
III. Tyrosine Kinase-linked Receptors
IV. Intracellular receptors regulating gene transcription

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Ligand-gated ion channels

Ligand-gated ion channels, which are membranebound receptors, directly linked to an ion channel
AKA: Ionotropic Receptors
Examples include the nicotine acetylcholine receptor,
glutamate receptor and the GABA-A receptor

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G-protein (Guanine nucleotide

regulatory protein) coupled receptors
Gprotein coupled receptors, which are membrane-bound
receptors coupled to G-proteins.
After activation of the G-proteins a variety biochemical
signal transduction pathways can be activated.
Many chemical messengers, like hormones and various
neurotransmitters, act through G-protein coupled
receptors.
AKA: Metabotropic Receptors Or 7-transmembrane
Receptors
Ex: Muscarinic acetylcholine receptors and adrenergic
receptors.
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Tyrosine Kinase-linked Receptors

Tyrosine kinase-linked receptors, are membrane bound
receptors and contain an intrinsic enzymatic function
(tyrosine kinase activity) in their intracellular domain.
Upon combination with ligand like insulin, the receptor is
activated and is able to phosphorylate tyrosine residues of
other intracellular proteins.
Protein phosphorylation is one of the underlying
mechanisms of the regulation of protein function.
Ex: Receptors for insulin and various cytokines and growth
factors.
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Intracellular receptors regulating

gene transcription
Intracellular receptors regulating gene transcription,
which are located in the cytosol.
Upon binding of the appropriate chemical e.g. steroid
hormones, the activated receptors translate to the
nucleus and initiate gene transcription.
AKA: Nuclear Receptors
Ex: Receptors for steroid hormones, thyroid
hormones and vitamin D.
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Different types of binding forces that

may exist in drug-receptor interactions
are as follows:
1.
2.
3.
4.
5.

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Covalent interactions
Ionic interactions
Hydrogen bonding interactions (non-ionic/neutral)
Vander Waals interaction
Hydrophobic/Lipophilic interactions

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Covalent interactions
These chemical forces may result in a temporary binding of the drug
to the receptor.
firm irreversible under biological conditions
covalent bond formation is rather rare except in a toxic situation
Examples:
a)
b)
c)

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A covalent bond is formed between the activated form of

phenoxybenzamine (-adrenergic receptor antagonist)
Antineoplastic or antibiotic drugs act mainly through the formation of
covalent bonds
The DNA-alkylating chemotherapeutic agents are chemically highly
reactive, forming covalent bonds with DNA functional groups. Such
covalently modified DNA may be incompatible with successful tumor
cell division
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Ionic interactions
Ionic bonds are formed by the attraction of opposite
charges in the receptor site with the ionized groups of the
drug molecule.
They are strong electrostatic interactions (5-10 kcal/mol)
and are responsible for relative orientation of the drug to
its binding site.
Electrostatic interactions tend to be much more common
than the covalent bonding in drug-receptor interactions.
Attraction between ions of opposite charge is inversely
proportional to the square of the distance between them.
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Ionic interactions (2)

Strong electrostatic interactions occur between
permanently charged ionic molecules.
The overall contribution of ionic interactions may be
overemphasized due to desolvation.
Ionic bonds have a relatively high stability.
Ex: In acetylcholine molecule, the positively charged
quaternary nitrogen may be attracted to the negative
charged ionized carboxyl group present in the
receptor site.
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Hydrogen bonding interactions

(non-ionic/neutral)
Polar-polar interactions are the attraction of opposite
charges.
The drug-receptor reaction is essentially an exchange
of the hydrogen bond between a drug molecule,
surrounding water, and the receptor site.
The hydrogen bond strength is distance dependent
may range from 5 7 kcal/mol, depending on the
binding environment
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Vander Waals interaction

These forces have the following characteristic
feutures:
a. Interactions at a close range
b. The Vander Waals interaction forces occur less
frequently than hydrophobic forces
c. Interactions are much weaker (~ 0.5-1 kcal/mol) than
other electrostatic interactions
d. Close contacts (attractive forces) over a large surface
area i.e. at the interface of ligand and binding site, may
contribute to binding
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Hydrophobic/Lipophilic interactions

hydrophobic bonds are formed between non-polar hydrocarbon

groups on the drug and those in the receptor site.
These bonds are not very specific but the interactions do occur to
exclude water molecules
Most of the drug molecules have a non-polar portion (alkyl or aryl
groups) which may combine with non-polar portion of the receptor
site through hydrophobic forces.
Hydrophobic interactions are generally weak, but important.
Hydrophobic interactions are probably significant in driving
interactions
a.
b.
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Between lipophilic drugs and the lipid component of biological

membranes
Between drugs and relatively nonpolar (non charged) receptor regions
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Receptor site theories

Occupation theory
Rate theory
Induced-fit theory

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Occupation theory
Clarks occupation theory
In this theory the receptorligand interaction is considered to be
a bimolecular interaction, in which the receptorligand complex
is responsible for the generation of the biological effect.
Clark assumed that the effects of a drug were proportional to
the fraction of receptors occupied by the drug.
Consequently, for a maximal effect the drug has to occupy all
receptors.
In Clarks theory, the agonist (A) interacts in a reversible way
with the receptor (R) and the formed complex (AR) gives rise to
the effect: A + R AR effect
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Rate theory
Rate theory was proposed by Paton and Rang in 1965.
According to this theory the most important factor in
determining drug action is the rate at which drug
receptor combination takes place.

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Induced-fit theory
This theory states that after combination, the
substrate induces a change in conformation of the
enzyme, leading to an enzymatically active
orientation of groups.
Ex: Acetylcholine may interact with the regulating
protein and alter the normal forces.

Macromolecular perturbation theory and activationaggregation theories are the extension of induced fit
theory.
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Physico-Chemical Properties of
Organic Medicinal Agents

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Pharmacologically Influential
Physico-chemical Properties of
Organic Medicinal Agents

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Solubility
Partition coefficient
Dissociation constant (pKa)
Hydrogen bonding
Molar refractivity (MR)
Ionization
Drug shape
Complexation
Surface activity
Protein binding
Bioisosterism.
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1. Solubility
the concentration of the dissolved solute, which is in
equilibrium with the solid solute
depends on the solute and solvent as well as temperature,
pressure, and pH
solubility of a substance is the ratio of these rate constants
at equilibrium in a given solution
solubility of an organic medicinal agent may be expressed
in terms of its affinity/ philicity or repulsion/phobicity for
either an aqueous (hydro) or lipid (lipo) solvent
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The most important intermolecular attractive

forces (bonds) that are involved in the
solubilization process are;

1.
2.
3.
4.

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Vander Waals attraction (induced dipole)

Dipole-Dipole Bonding
Ionic Bonding
Ion-Dipole Bonding

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Vander Waals attraction

(induced dipole)
are weakest intermolecular forces (0.51.0 kcal/mole)
which occur between nonpolar groups (e.g.
hydrocarbons)
are highly distance and temperature dependent

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Dipole-Dipole Bonding
occur when electronegative elements are attached to
carbon
are stronger (1.0 to 10 kcal/mole) and occur
electrostatically between electron deficient and
electron rich atoms (dipoles)
Hydrogen bonding is a specific example of this
bonding and serves as a prime contributor to
hydrophilicity
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Ionic Bonding
Ionic bond is electrostatic attraction between cations and
anions.
These ionic attractions are common in inorganic
compounds and salts of organic molecules and are
relatively strong (5 kcal/mole).
the most important factor in the prediction of water
solubility in ionic drugs is their ability to ionize
The degree of ionization of a drug is by far the best predictor
of solubility for most compounds, which are acidic or basic
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Ion-Dipole Bonding
is electrostatic force between a cation/anion and a dipole.
is relatively strong (1-5 kcal/mole) and is low temperature
and distance dependent
is an important attraction between organic medicinal
agent and water
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 organic medicinal agent with
lipid and/or aqueous phases
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Methods to Improve the Solubility of Drugs:

Structural Modifications

A.
B.
C.
D.
E.

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alter the chemical structure of the molecule

reduce intramolecular forces
Use of Co-solvents
Employing surfactants
Complexation

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Methods to Improve the Solubility of Drugs:

Structural Modifications
A. alter the chemical structure of the molecule
The addition of polar groups like carboxylic acids,
ketones and amines can increase solubility by increasing
hydrogen bonding and the interaction with water.

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Methods to Improve the Solubility of Drugs:

Structural Modifications

B. reduce intramolecular forces

methyl dopa (solubility ~10 mg/ml) and methyl dopate
(solubility 10-300 mg/ml) depending on pH addition of
the ethyl ester to methyldopa reduces the
intramolecular hydrogen bond between the carboxylic
acid and primary aminereduces the melting point and
increases solubility.

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Methods to Improve the Solubility of Drugs:

Structural Modifications

C. Use of Co-solvents
addition of a co-solvent can increase solubility of
hydrophobic molecules by reducing the dielectric
constant of the solvent
Some problems with the use of co-solvents are
precipitation of the drug with dilution of solvent mixture
and tissue damage or pain upon injection This dilution
occurs after administration of the drug into the body
Commonly used co-solvents are propylene glycol,
polyethylene glycol, ethanol and sorbitol
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Methods to Improve the Solubility of Drugs:

Structural Modifications

D. Employing surfactants
A surfactant or surface active agent is amphiphilic,
meaning it has polar end (the circular head) and a
nonpolar (the tail).
When a surfactant is placed in water it will form
micelles.
A nonpolar drug will partition into the hydrophobic core
of the micelle and will get solubilized.

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Methods to Improve the Solubility of Drugs:

Structural Modifications

Complexation
Complexation relies on relatively weak forces such as
London forces, hydrogen bonding and hydrophobic
interactions.
As the concentration of complexing agent is increased,
so is the solubility
In some cases however, the complex can precipitate out
from solution as the concentration of complexing agent is
increased.
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Importance of Solubility

1. governs the preparation of solutions as a dosage

form
2. Drugs must be in solution to interact with receptors

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2. Partition coefficient
as the equilibrium constant of drug concentrations
for unionizable molecules in the two phases
P=

and

for ionizable molecules (acids,

bases, salts), where alpha () is the degree of

ionization in aqueous solution.
It is basically a constitutive property
P=
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 ability of a drug to dissolve in a lipid phase when an

aqueous phase is also present Lipophilicity
The lipophilicity can be best characterized by partition
coefficient

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3. Dissociation Constant
is one of the most important characteristics of a pharmaceutical
Compound
Majority of drugs are weak acids or weak bases and like acetic
acid or ammonia, they react with water to form conjugate pairs.
The pKa or Dissociation constant is a measure of the strength
of an acid or a base and is sometimes called the acidity constant
or the ionization constant.
It is a numerical representative of the relative proton transfer for
that substance,or the likelihood of that compound donating a
proton.
It is calculated in the same manner as the equilibrium constant
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3. Dissociation Constant (2)

Weakly acidic and basic drugs ionize only slightly in the
presence of water
Conductivity, freezing point depression, pH of solution,
and spectrophotometric data may be used to determine a
compounds dissociation constant.
The ratio of ionized over unionized form affects drugs
solubility, permeability, binding, and other characteristics.
The pKa allows to determine the charge on a molecule at
any given pH.
Note: pKa and Log P measurements are useful parameters in
understanding the behavior of drug molecules.

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4. Hydrogen Bonding
hydrogen bond is a special type of dipole-dipole
interaction between the hydrogen atom in a polar
bond such as NH, OH, or FH and an
electronegative atom O, N, or F atom.
This interaction is written as AH B

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4. Hydrogen Bonding (2)

A and B represent O, N or F. AH is one molecule (or)
part of a molecule and B is a part of another
molecule; and the dotted line represents the
hydrogen bond.
These three atoms usually lie along a straight line, but
the angle AHB can deviate as much as 30 from
linearity

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Ex: Hydrogen bonding in

NH3, H2O and HF

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Types of H-bonding

A. Intermolecular hydrogen bonding

B. Intramolecular hydrogen bonding

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Intermolecular hydrogen bonding

hydrogen bonding occurs between two or more than two molecules
of the same compound and results in the formation of polymeric
aggregate
Hydrogen bonding in ammonia
Hydrogen bonding in water

it increases the boiling point of the compound and also its solubility
in water
The molecules that are able to develop intermolecular hydrogen
bonding improve their solubility by the formation of intermolecular
hydrogen bonding with water.
Ex: Ethanol shows higher boiling point and higher solubility in water
than dimethyl ether even though both have the same molecular
weight
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Intramolecular hydrogen bonding

hydrogen bonding occurs with in two atoms of the same
molecule.
This type of hydrogen bonding is commonly known as
chelation and frequently occurs in organic compounds.
Sometimes intramolecular hydrogen bonding develops a
six or 5-membered ring
Ex:
Hydrogen bonding in o-chlorophenol
Hydrogen bonding in o-nitro phenol
Hydrogen bonding in 2, 6 dihydroxy benzoic acid
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Intramolecular hydrogen bonding

decreases the boiling point of the compound and also
its solubility in water.
This is because of the fact that the chelation between
the ortho substituted groups restricts the possibility
of intermolecular hydrogen bonding with water and
thus prevents association of the molecules, which
would have raised the melting point, boiling point

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Effects of hydrogen bonding

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Boiling and melting points

Water solubility
Strength of acids
Spectroscopic properties
Surface tension and Viscosity
Biological products
Drug-Receptor interactions
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H-Bonding and
Boiling and Melting points
Intermolecular hydrogen
bonding increases the boiling
point of the compound due to
association of several
molecules of the same
compound.
As a result the intermolecular
forces are increased and hence
more energy (large amount of
heat) is required to dissociate
the molecules for vaporization
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Intramolecular hydrogen
bonding decreases the boiling
point of the compound
because of the fact that the
chelation between the groups
of same molecule restricts the
possibility of intermolecular
hydrogen bonding and thus
prevents association of the
molecules, which would have
raised the melting point and
boiling point.
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H-Bonding and
Water solubility
Solubility of a substance increases tremendously
when hydrogen bonding is possible between the
solvent and the solute.
Ex: Methanol and ethanol are highly soluble in water
due to hydrogen bonding between molecules.
The high solubility of polyhydric phenols and sugars
may be attributed to the fact that these compounds
make available greater number of OH groups for
hydrogen bonding
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H-Bonding and
Strength of acids
if the anion of acid were stabilized due to
intramolecular hydrogen bonding, there would be
marked increase in the strength of acid.
Ex: The ionization constant of salicylic acid is higher
than the other two isomers and is 17 times more
acidic than benzoic acid.

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H-Bonding and
Spectroscopic properties
The hydrogen bonding shifts the position of bands in
infrared and NMR spectra of organic compounds.
Ex: Infrared spectrum of ethyl alcohol in vapour phase
shows absorption band at 3700 cm1 due to free
hydroxyl group. In solution this band is completely
replaced by a broad band around 3500 cm1 which is
characteristic of hydrogen bonded hydroxyl groups

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H-Bonding and
Surface tension and Viscosity
The compounds which possess hydrogen bonding are
found to have higher surface tension and viscosity
Glycerol, glycol, sulphuric acid, sugar syrup,
phosphoric acid, etc., are viscous liquids due to
extensive hydrogen bonding between their molecule
Due to more number of hydroxyl (OH) groups, the
extent of hydrogen bonding is more in glycerol it is
more viscous than glycol
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H-Bonding and
Biological products
The three dimensional structures of proteins and nucleic acids is
due to hydrogen bonding.

In -helices, hydrogen bonds extend from the hydrogen atoms of

polar NH units in peptide group to oxygen atoms of polar
carbonyl units

Hydrogen bonds are extremely important in the chemistry of the

genetic code.

The double strands of DNA are held together by hydrogen bonds.

The replication of DNA depends on hydrogen bonds which
selectively connect specific base pairs, as do the several steps by
which the genetic message determines the specific order of
amino acids in a protein

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H-Bonding and
Drug-Receptor interactions
Hydrogen bonding is also a secondary binding force in
drug-receptor interactions

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5.Molar Refractivity
is the molar volume connected by the refractive index
it represents size and polarizability of a fragment or
molecule
Originally proposed by Pauling and Pressman as a
parameter for the correlation of dispersion forces
involved the binding of haptens to antibodies
it is determined from the refractive index, the
molecular weight, and the density of a crystal
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5.Molar Refractivity (2)

Since refractive index doesnt change much for
organic molecules, the term is dominated by the MW
and density.
Larger MW, larger the steric effect and greater the
density.
A smaller MR for the same MW indicates stronger
interactions in the crystal (larger density indicates
that the packing is better due to stronger
interactions)
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6. Ionization of Drugs
ionization of a drug is dependent on its pKa and the
pH
The ratio of ionized/ non ionized drug may be
determined by the Henderson- Hasselbalch
relationship
accumulation of an ionized drug in a compartment of
the body is known asion trapping

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Importance of ionisation of drugs

1.
2.

The lower the pH relative to the pKa greater is the fraction of

protonated drug (protonated drug may be charged or
uncharged)
weak acid at acidic pH : more lipid-soluble, becauses it is
unchargedthe uncharged form more readily passes through
biological membranes.
Note that a weak acid at acidic pH will pick up a proton and
become unchargedRCOO + H+ RCOOH

3.

weak base at alkaline pH : more lipid-soluble, because it is

unchargedthe uncharged form more readily passes through
biological membranes.
Note that a weak base at more alkaline pH will lose a proton,
becoming uncharged RNH3+ RNH2 + H+

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7. Drug Shape
The three-dimensional shape of the drug is thought to
interact with a complementary structural binding
region of the receptor, typically a protein.
The specific nature of the interaction defines whether
the drug acts as an agonist promoting a change in
cellular function or as an antagonist, which blocks the
receptor usually resulting in no direct biological effect

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8.Complexation
Complexes or coordination compounds result from a
donor-acceptor mechanism (donatingaccepting
electron or, rather, an electron pair) or Lewis acidbase reaction (donating-accepting).
Any non-metallic atom or ion, whether free or contained
in a neutral molecule or in an ionic compound, that can
donate an electron pair, may serve as the donor.
The acceptor, or constituent that accept the pair of
electrons, can be a metallic ion or sometimes also a
neutral molecule
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9. Surface Activity
SURFACTANT material that can greatly reduce the
surface tension of water when used in very low
concentration
Components:
Water soluble Hydrophilic
Water insoluble Hydrophobic

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Hydrophobe

is usually the equivalent of an 8 to 18 carbon

hydrocarbon (aliphatic, aromatic or mixture of both)
Sources:
Natural fats and oils
Petroleum fractions
Relatively short synthetic polymers
Relatively high molecular weight synthetic alcohols

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Hydrophile

can be anionic, cationic or non-ionic in nature

Anionic carboxylates (soaps), sulphates, sulfonates
and phosphates
Cationic some of amine products
Non-ionic associated with water at the ether oxygens
of a polyethylene glycol chains

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10. Protein Binding

Depending upon whether the drug is weak or strong
acid or base, or is neutral, it can bind to a single blood
protein, to multiple proteins
Multiple proteins:
Serum Albumin acidic or basic drugs
Acid-glycoprotein (AGP) basic entities
Lipoproteins both basic and neutral drugs

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10. Protein Binding

The extent to which a drug is bound to plasma proteins
can affect the distribution of drugs
The drug-protein complex does not permeate through
phospholipid bilayer (capillary membranes, glomerular
membranes in the nephrons, and the blood brain barrier)
Bound drugs are also less available to the enzymes involved in
first pass metabolism
Higher protein binding activity greater half life

The fraction of the drug which is bound to the protein is

incapable of crossing cell membrane and cannot bind with
receptors
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11. Bioisosterism
ISOSTERISM two molecules or ions or radicals
having the same number and arrangement of
electrons
BIOISOSTERISM application of the concept of
isosterism to biological activity

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CHEMISTRY

PRODRUGS

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Prodrugs

are pharmacologically inactive derivatives of active

drugs
are designed to maximize the amount of active drug
that reaches its site of action, through manipulation
of the physicochemical, biopharmaceutical or
pharmacokinetic properties of the drug
are converted into the active drug within the body
through enzymatic or non-enzymatic reactions
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various applications of prodrug

approach
1. Improved physicochemical properties (e.g., better
solubility in the intended formulation)
2. Enhanced delivery characteristics and/or therapeutic
value of the drug
3. To improve drug penetration through biological
membranes
4. To increase site specificity of the drug
5. To improve the drugs stability and solubility
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various applications of prodrug

approach (2)
6. To increase duration of pharmacological activity
7. To decrease the drugs toxicity and adverse effects
8. To improve patient acceptance

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An ideal prodrug must meet the

following requirements:
1. The prodrug is inactive or less active than the parent
compound
2. The linkage between the drug and the carrier must
be cleaved in vivo
3. The carrier molecule released in vivo must be nontoxic
4. The metabolic fragments of carrier molecule, apart
from the drug should be non-toxic
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Classification of Prodrug
(functional group)
1.
2.
3.
4.

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Carboxylic acids and alcohols

Amines
Azo Linkage
Carbonyl compounds

117

Carboxylic acids and alcohols

can be prepared by conversion to an ester
ester can be easily hydrolysed by esterase enzymes (ester hydrolase,
lipase, cholesterol esterase, acetylcholinesterase, carboxypeptidase)
present in plasma and other tissues to give active drug

Antibiotic prodrugs comprise the largest group of prodrugs

developed to improve oral absorption
Pivampicillin, talampicillin and bacampicillin are prodrugs of ampicillin, all
resulting from the esterification of the polar carboxylate group.
The absorption of these prodrugs is nearly complete (98-99%) whereas
that of ampicillin is < 50%.

Enalapril (ACE inhibitor) is the ethyl ester prodrug of the active

diacid, enalaprilat.
Enalaprilat is poorly absorbed from the gastrointestinal tract (<10%), but
absorption of the prodrug enalapril is greatly improved (60%)
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Amines

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Azo Linkage

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Carbonyl compounds
Carbonyl functionalities such as aldehydes and
ketones are converted to prodrugs
These prodrugs are reconverted to the carbonyl
compounds by hydrolysis
Ex: Methenamine releases HCHO in the urine, which acts
as an antibacterial agent

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Some important prodrug concepts

are:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
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To Improve patient acceptance

To reduce gastric irritation
To improve chemical stability
Prodrugs for increased water solubility
To decrease drugs toxicity and adverse effects
To improve membrane transport
Prolonged Activity
Tissue specific prodrug design
Prodrug design based on site specific conditions
Enzyme specific prodrug design
122

To Improve patient acceptance

Two approaches can be utilized to overcome the bad
taste of drug:
1. reduction of drug solubility in saliva
2. to lowers the affinity of drug towards taste receptors

Ex. : Clindamycin has bitter taste, so it is not well

accepted by children. It was found that by increasing
the chain-length of 2-acylesters of clindamycin, the
taste improved from bitter to non-bitter taste
(phosphate ester)
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To reduce gastric irritation.

Several drugs (NSAIDS, nicotinic acid, kanamycin,
diethylstilboestrol) cause irritation and damage to
gastric mucosa
Ex. : Salicylic acid to aspirin

Ex. : Nicotinic acid to nicotinic acid hydrazide

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To improve chemical stability

Ex. : Azacytidine (antineoplastic drug) in aqueous
solution is readily hydrolyzed but its bisulphite
prodrug is stable.

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Prodrugs for increased water

solubility
Drugs with hydroxyl functional group can be
converted into their hydrophilic forms by use of halfesters such as hemiglutarates or hemiphthalates ; the
other half of these acidic carriers can form sodium,
potassium or amine salts and render the moiety water
soluble

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Prodrugs for increased water

solubility (2)
Ex. : Prednisolone and methylprednisolone are poorly
water-soluble corticosteroid drugs.
Prednisolone phosphate is a water-soluble prodrug of
prednisolone that is activated in vivo by phosphatases.

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To decrease drugs toxicity and

adverse effects
Ex. : Dipivaloylepinephrine prodrug instead of
epinephrine to treat glaucoma

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To decrease drugs toxicity and

adverse effects (2)
Ex. : Esterification of aspirin greatly suppresses gastric
uterogenic activity

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To improve membrane transport

Barbiturates

Hexobarbitone was found to be an effective drug but its

membrane permeability was found to be low.
However N-methylhexobarbitone a simple derivative of the
parent drug was found to have better permeability
characteristics.
After intake, the N-methyl group is cleaved in the liver to
release the physiologically active drug

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To improve membrane transport (2)

Dopamine
Prodrug: L-3,4-dihydroxyphenylalanine (Levo-DOPA)
has better blood-brain permeation characteristics
since it uses amino acid channels for transportation
Once inside the cell, decarboxylase enzyme removes the
acid group to generate dopamine.

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Prolonged Activity
Ex: Nordazepam
Prodrug: Diazepam Due to presence of N-methyl
group the prodrug resists quick degradation
Slow release of the nordazepam in the liver by
demethylation prolongs body retention characteristics

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Tissue specific prodrug design

Ex: Dexamethasone and prednisolone
Prodrug: dexamethasone-21--glucoside and
prednisolone-21--glucoside
are hydrophilic in nature and therefore are absorbed poorly
in intestine.
The glucosidase enzymes present in the bacteria located in
colon release the parent hydrophobic drugs for absorption
in the area

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Prodrug design based on site specific

conditions
Ex: Tyrapazamine has been developed as a cytotoxic
agent.
It has two N-oxide moieties, which on reduction gets
converted to highly reactive diradicals.
The diradicals are responsible for cleavage of DNA

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Enzyme specific prodrug design

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DRUG METABOLISM

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Metabolism
AKA: biotransformation
the bodys mechanism for processing, using,
inactivating, and eventually eliminating foreign
substances
the process of polarization of a drug.
This results in the formation of a metabolite that is more
polar and, thus, less able to move into tissues and more
able to be excreted from the body

a major mechanism of drug elimination

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Drug metabolism
basically a process that introduces hydrophilic
functionalities onto the drug molecule to facilitate
excretion
a detoxification function the human body possesses
to defend itself from environment hostility

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Sites of Metabolism

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Liver the primary site for metabolism

Gastrointestinal tract (epithelial cells lining)
Kidneys
Lungs

140

Metabolic Reactions
Phase I
Phase II

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Phase I metabolism
the predominant pathway of biotransformation
The enzymes involved are primarily located in the
endoplasmic reticulum of the liver cell Microsomal
Enzymes
are non-synthetic in nature, and generally produce more
water soluble and less active metabolite
Reactions involved:
a. Oxidative processes
b. Reductive processes
c. Hydrolytic reactions
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Oxidative Processes

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aromatic hydroxylation
aliphatic hydroxylation
N, O, and S-dealkylation
N-hydroxylation
N-oxidation
Sulfoxidation
Deamination
Dehalogenation
143

Reductive Processes
azodye-reduction
nitroreduction

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Oxidation

is normally the first step of drug metabolism

Mixed-function oxidases or monooxygenases is an
important complex enzyme catalyses metabolic
oxidation of a large variety of endogeneous
substances (steroidal hormones) and exogeneous
substances (drugs)

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Oxidation of carbon-heteroatom
systems
Carbon-heteroatom systems (N, O, S) are commonly
present in many drugs.
They are metabolized by any of the following oxidation
processes :
a.

Oxidation or hydroxylation of heteroatom:

Ex: N-oxidation, N-hydroxylation, S-oxidation

b. Hydroxylation of carbon atom attached to the heteroatom

followed by cleavage of carbon-heteroatom bond.

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Ex: N-dealkylation, S-dealkylation, O-dealkylation

146

N-Hydroxylation
Drugs containing non-basic nitrogen atom (amides),
non-basic aromatic amines and basic amines are
metabolized by N-hydroxylation

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Example 1

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Example 2

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Example 3

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N-Oxidation
Compounds possessing of basic nitrogen are
metabolized by N-oxidation process

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Ex: Tertiary amines yield N-oxides

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S-Oxidation
Compounds possessing of carbon-sulfur bonds are
metabolized to sulfoxides by S-oxidation.
The sulfoxides may be excreted as urinary
metabolites or oxidized to sulfones (SO2)

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Dealkylations
second type of oxidative biotransformation
S-Dealkylation
N-Dealkylation
O-Dealkylation

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S-Dealkylation
involves oxidative cleavage of alkyl carbon-sulfur
bonds

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N-Dealkylation
primary or secondary amines dealkylation of an
alkylgroup starts at the carbon adjacent to the
nitrogen
tertiary amines with hydroxylation of the nitrogen
The intermediate products are labile and break up
into the dealkylated amine and aldehyde

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O-Dealkylation
O-Dealkylation of drugs possessing CO bond
involves hydroxylation of -carbon to form an
unstable hemiacetal or hemiketal intermediates.
These intermediates spontaneously cleave to form
alcohol and carbonyl compound

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Aromatic Hydroxylation
(Oxidation of Aromatic Carbon Atoms)

is oxidation of aromatic compounds into phenols

through the intermediate formation of highly reactive
immediate i.e. arene oxide

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Many drugs containing phenyl groups (phenylbutazone,

phenytoin, amphetamine, phenformin etc.) are
metabolized by aromatic hydroxylation

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Oxidation of benzylic carbons

The carbons directly attached to aromatic rings are
oxidized to aldehydes and carboxylic acids via
alcohols.

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Example 1

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Example 2

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Oxidation of olefins
Drugs possessing carbon-carbon double bonds are
oxidized to 1,2-diols through formation of epoxides
Ex: Carbamazepine is oxidized to trans-10, 11-dihydroxy
carbamazepine via carbamazepine-10, 11-epoxide

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Reductive reactions
Drugs containing carbonyl, nitro, and azo groups are
metabolized by reduction to alcohols and amines
respectively.
The reduced compounds are conjugated and
eliminated from the body.

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Example 1

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Example 2

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Example 3

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PHASE II REACTIONS
Aka: Conjugation reactions
are synthetic reactions where the product or the
metabolite from Phase I gets conjugated
Always produces a large, polar, metabolite that is
readily excreted from the body
occurs by glucuronidation, sulfation, aminoacid
conjugation, acetylation, methylation or glutathione
conjugation to facilitate elimination
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PHASE II REACTIONS (2)

introduces hydrophilic functionalities such as
glucuronic acid, sulfate, glycine, or acetyl group onto
the drug or drug metabolite molecules
are catalyzed by a group of enzymes called
transferases
trasferases are located in cytosol, except the one
facilitates glucuronidation, which is a microsomal
enzyme
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Glucuronidation
involves conjugation of metabolite or drug molecule with
glucuronic acid
glucuronic acid molecule is transferred to the substrate from a
cofactor (uridine-51-diphospho--D-glucuronic acid)

Is catalyzed by various microsomal glucuronyl transferases

Glucuronides are generally inactive and are rapidly excreted into
the urine and bile.
Molecules associated with phenolic hydroxyl, alcoholic hydroxyl,
and carboxylic acid groups undergo glucuronidation reaction
The enzyme that catalyzes this reaction is uridine diphosphate
glucuronosyltransferase (UGTs)
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Glucuronidation (2)

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Glucuronidation (3)

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Sulfate Conjugation
involves transfer of a sulphate molecule from the
cofactor (31- phosphoadenosine-51-phosphosulfate)
to the substrate (metabolite or drug moiety) by the
enzymes (sulfotransferases)
is the common conjugation reactions of substrate
molecules possessing of alcoholic hydroxyl, phenolic
hydroxyl and aromatic amine groups

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Sulfate Conjugation (2)

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Hydrolysis
The enzymes involved in hydrolysis are esterases,
amidases, and proteases.
These reactions generate hydroxyl or amine groups,
which are suitable for phase II conjugation

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Acetylation
is an important metabolic pathway for drugs
containing primary amino groups.
The acetylated conjugates are generally non-toxic and
inactive.
Ex: histamine, procainamide, para aminosalicylic acid
(PAS), hydralazine, isoniazid

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CYTOCHROME P450 REDUCTASE

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CYTOCHROME P450s [CYPs]

are membrane bound proteins with an approximate
molecular weight of 50 kD, and contain a heme moiety.
There are about 30 human cytochrome P450 enzymes out
of which only six, CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1 and CYP3A4 are the metabolising enzymes
involves in the metabolism of many drugs and dietary
substances, and in the synthesis of steroid hormones and
other extracellular lipid signalling molecules

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The following table shows the major

CYPs involved in the metabolism
of some known drugs

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factors affecting the rate of drug

metabolism
1.
2.
3.
4.
5.

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Physicochemical properties of drugs

Chemical factors
Diet
Genetic or hereditary factors
Environmental factors

181

Physicochemical properties of drugs

Molecular size, shape, acidity or basicity, lipophilicity,

pKa, and steric and electronic characteristics of drugs
influence its interaction with the active sites of
enzymes.

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Chemical factors
A large number of chemical substances such as drugs,
insecticides etc. can increase the rate of drug
metabolism due to increased rate of formation of
newer enzymes or decreased rate of degradation of
drug metabolising enzymes.
Ex. Alcohol enhances metabolism of phenobarbitone,
phenytoin etc.

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Diet
The enzyme content and activity is altered by a
number of dietary compounds.
Fat free diet depresses cytochrome P450 levels since
phospholipids, which are important components of
microsomes become deficient.

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Genetic or hereditary factors

are the most significant factors in drug metabolism
Genetic differences among individuals or ethnic
groups can lead to an excessive or prolonged
therapeutic effect or toxic overdose.
Ex: The enzyme CYP2D6 metabolises a large number of
drugs.
The activity of this enzyme varies widely among ethnic
groups.
About 1% of Arabies, 30% Chinese and 7-10% caucasions are
poor metabolizers of CYP2D6 drugs.
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Environmental factors
Environmental factors such as smoking, alcohol
consumption and concomitant drug therapy also
influence the outcome of drug metabolism.
Ex: Cigarette smoke produces polynuclear aromatic
hydrocarbons.
CYP1A2 metabolises the polynuclear aromatic
hydrocarbons to carcinogens responsible for lung and
colon cancer.

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