Medicinal chemistry-pharmacokinetics & pharmacodynamics

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Dr. G. Krishnaswamy, DOS & R in Organic Chemistry, TUT Page 1
Medicinal/Pharmaceutical chemistry deals with the discovery, design, development
and both pharmacological and analytical characterisation of drug substances.
Pharmacokinetics (PK) is the study of the disposition of a drug after its delivery to an
organism—in short, a study of what “the body does to a drug”.
Pharmacodynamics (PD) is the quantitative study of the relationship between drug
exposure (concentrations or dose) and pharmacologic or toxicologic responses- —in
short, a study of what “drug does to the body”.
Drug is a substance which also cures the disease but is habit forming, causes addiction
and has serious side effects.
Medicine is a chemical substance which cures the disease, is safe to use, has negligible
toxicity and does not cause any addiction.
All medicines are drugs but all drugs are not medicines.
Difference between Drug and Medicines
Drug Medicine
Drug = Active potent compound Medicine = Active Pharmaceutical
Ingredient + Excipient
Drug does not have any definite form
and dose.
Medicine has a definite form and dose.
Drugs are the active potent compounds Medicines are the administrative form
of drug
All drugs are not medicines All medicines are drugs
Not always useful Always useful
Hydrophobic (Lipophilic): Molecules are lipid soluble and can easily cross the plasma
membrane.
Hydrophilic (Lipophobic): Molecules that are water soluble and do not readily cross the
plasma membrane.

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Pharmacokinetics (PK) involves 4 distinct stages i.e. ADME
1. Absorption – How the drug gets into the blood by crossing cell membrane
2. Distribution – How the drug is transported through the blood
3. Metabolism – How the drug is modified by the body.
4. Excretion – How the drug is permanently removed from the body.
Before study of drug absorption a brief look at the way or path by which the drug moves
is needed i.e. route of drug administration.
Routes of Drug Administration
Drugs can be administered upon or into the body by a variety of routes, to produce effect
locally or systemically.
Drugs can be applied on the skin and mucus membrane to produce localized effects. This
is called local route of administration.
When drugs are given through mouth (oral route) or by injections (parenteral route) they
are absorbed into the blood stream and are distributed throughout the body fluids. Such
effect produced by the drug is called systemic effect.
The choice of appropriate route in a given situation depends both; on drug as well as
patient related factors.
Factors governing selection of the route
1. Physical and chemical properties of the drug.
2. Site of desired action of the drug: localized/systemic and accessibility/
inaccessibility.
3. Rate and degree of absorption of drug from different routes.
4. Effect of digestive enzymes and liver metabolism on the drug.
5. Precision of dosage required.
6. Condition of patient
The major routes of drug administration are
1. TOPICAL ROUTE (LOCAL ROUTE):
These routes can be used for desired localized effect at the specific site which is
easily approachable. Thus, the drug affects mostly the part it comes in contact

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with or surrounding, without exposing the rest of the body. Consequently, there
will be no or minimal systemic side.
i) Dermal and inunction (skin)
ii) Conjunctival (eye), Nasal (nasal mucosa), Auditory (ear)
iii) Vaginal, anal and urethral
2. ENTERAL ROUTE:
When the drug is placed directly into any part of the gastrointestinal tract (G.I.T.)
is called an ‘Enteral’ route of administration (enteron= intestine).
i) Oral
ii) Sublingual / Buccal
iii) Rectal
3. PARENTERAL ROUTES
Drug administered by injections is conventionally referred to as parenteral route.
Routes other than the “enteral” are called “parenteral” routes of administration.
(Par= beyond, enteral = intestinal).
(A)Injections
i) Intravenous - Injected through lumen of vein
ii) Intramuscular – Injection given either in arm or thigh.
iii) Intraperitoneal – Injected into peritoneal space in the abdomen.
iv) Subcutenous – Injected into subcutenous tissue under the skin.
v) Intra arterial – Injected into desired lumen of artery
vi) Intra medullary – Injected into medullary cavity of sterna bone
vii) Intra articular – Injected directly into the joint space.
(B) Intra nasal – Administration drug directly into nose.
(C)Inhalation – Systemic use of drug through lungs.
(D)Transdermal – Administration is considered under parenteral route because
the patches though applied topically provide systemic effect.

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DRUG ABSORPTION
Drug absorption refers to the transfer of drugs from the site of administration into the
systemic circulation (blood stream).
The rate and extent of absorption depends on the route of administration, the
formulation and chemical properties of the drug, and physiologic factors that can impact
the site of absorption. When a drug is administered intravenously, absorption is not
required because the drug is transferred from the administration device directly into the
bloodstream. In the case of intravenous administration, the entire dose of the drug is
available to move to the sites of drug action. Administration by other routes may result
in less availability due to incomplete absorption.
Factors influencing drug absorption
1. Pharmaceutical factor
This includes nature of drug, particle size, surface area of the drug, type of dose
form (solution, suspension, capsule and tablet), excipient and process used in
manufacturing of drug delivery system.
When a drug administered orally via tablet, capsule or suspension the rate of
absorption is controlled by how fast the drug particles dissolve in the fluid. Hence,
the dissolution rate is the rate limiting step.

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2. Drug Factor
Factors which control the dissolution are solubility, ionization and surface area.
The cell membrane is mostly made of fatty molecules. Hence, the non ionized
molecules which are lipid soluble that is able to penetrate across the membrane
while ionized molecules are water soluble.
Since most of the drugs are either weak acids (Eg:- Aspirin) or weak bases (Eg:-
Codeine), they undergo dissociation in solution. The extent to which the drug
undergoes ionization depend upon the pH of the solution.
Weak organic acids are usually absorbed primarily across the stomach. Since, the
pH ranges from 1 to 3 in the stomach.
COOH
OCOCH3
COO-
OCOCH3
H+
Unionized form
Lipid soluble
Ionized form
Water soluble
Weak organic bases are absorbed primarily across the intestine because pH is in
the range of basic (pH - 5 to 8).
R NH2
H+
R NH3
+
Unionized form
Lipid soluble
Ionized form
Water soluble

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3. Biological factor
(i) Surface area
(ii) Gastric emptying time
(iii) Presence of food
(iv) First pass metabolism
DRUG TRANSPORT
When a drug is in soluble state, it must pass through one or more biological membranes,
to be absorbed and distributed into organs and tissues. Drug molecules can cross cell
membrane by various transport mechanisms. Such movement of the drug across the
membrane is called as drug transport.
The cell membrane consists of two layers of phospholipids with proteins and sugars
embedded in them. In addition to phospholipids, the lipid cholesterol is also present. The
phospholipid molecules have a head, which is electrically charged and hydrophilic
(water loving), and a tail which has no charge and is hydrophobic (water hating). The
phospholipid bilayer is arranged like a sandwich with the hydrophilic heads aligned on
the outer surfaces of the membrane and the hydrophobic tails forming a central water
repelling layer. These differences influence the transfer of substances across the
membrane.
The three broad categories of drug transport mechanisms involved in absorption are:
1. Transcellular or Intracellular transport: Transcellular or Intracellular
transport is defined as the passage of drugs across the GI epithelium. It is
the most common pathway for drug transport.

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2. Paracellular or intercellular transport: Paracellular or intercellular
transport is defined as the transport of drugs through the junctions between
the GI epithelial cells.
3. Vesicular transport: Vesicular transport is an energy dependent process
but involves transport substances within vesicles into a cell.

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A. Passive transport process
This type of transport process does not require energy to traverse through the lipid
bilayer. These are further classified as:
1. Passive diffusion
Passive diffusion or non-ionic diffusion is considered as the major absorption process for
more than 90% of drugs.
It is the movement of the drug molecule from a region of higher concentration to a
region of lower concentration. Concentration gradient or electrochemical gradient is
considered as the driving force for this process.
Passive diffusion is expressed by Fick’s law of diffusion which states that “The drug
molecules diffuse from a region of higher concentration to lower concentration until
equilibrium is attained & rate of diffusion is directly proportional to the concentration
gradient across the membrane”
dq
dt
=
D A Ko/w
h
(CGIT - CP)
Where
dQ/dt represents the rate of drug diffusion (amount/time) and it also shows the rate of appearance of the
drug in blood.
D represents the diffusion coefficient of the drug through the membrane (area/time).
A represents the surface area of absorbing membrane for diffusion of drug (area).
Ko/w represents the partition coefficient of the drug between the lipid membrane and the aqueous GI
fluids. It has no unit.
(CGIT-CP) represents the difference in the concentration of drug in the GI fluids and the plasma and is often
called as the concentration gradient.
h represents the thickness of the membrane (length).

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2. Pore transport
Pore transport is also called as convective transport, bulk flow or filtration. This
transport mechanism is responsible for the transportation of drug molecules via the
protein channels into the cell.
3. Ion-pair transport
Absorption of some highly ionized compounds is known to penetrate the membrane
despite low lipid-water coefficient. It is postulated that these highly lipophobic drugs
combine reversibly with endogenous compound forming neutral ion pair complexes.
This neutral complex penetrates the lipid membrane by passive diffusion.
4. Facilitated or Carrier-mediated transport
The presence of some specialized transport mechanisms is suggested by the fact that
some polar drugs traverse the cell membrane more easily that anticipated from their
concentration gradient and partition coefficient values. This mechanism involves a
membrane involves a membrane component called as carrier which binds to the solute
molecules reversibly or non-covalently. This complex crosses the membrane and then

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dissociates to release the solute molecule to the other side of the membrane. Carrier is
then returned to the initial position across the membrane to start the cycle again.
Facilitated diffusion is a simple carrier mediated transport mechanism. The main
features of this transport system is that transport occurs along the No energy expenditure
is involved, because driving force is concentration gradient. This process is known as
downhill transport process.
B. Active transport processes
Active transport process is a transport process in which materials are transported against
the concentration gradient i.e. from a region of lower concentration to a higher
concentration. It is also known as uphill transport. It uses energy from ATP to pull
molecules from extracellular to intracellular side.
In general, drugs will not be actively transported unless they sufficiently resembles
endogenous substances that are normal substrate for the particular carrier system.
C. Vesicular or corpuscular transport (Endocytosis)
Like active transport these process also involves the use of energy but differs in the case
that it transports substances within the vesicles into the cell.
Vesicular transport can be further distinguished into two categories such as:
1. Fluid or Pinocytosis (cell drinking): Pinocytosis is a non-specific process
whereby a substrate enters a cell by invagination to form an intracellular vesicle.

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2. Adsoptive or Phagocytosis (cell eating): In phagocytosis adsorptive uptake of
solid substances takes place.
The particle or drug within the vesicle released intracellularly possibly through lysosomal
digestion of the vesicle membrane or by intermembrane fusion.
DRUG DISTRIBUTION
After entry of drugs into systemic circulation by different routes including intravascular
injection or oral administration or any of the various extravascular sites, the drug enters
into a number of processes called disposition processes.
The process involved in the disposition are-
Distribution- It is defined as the reversible transfer of drug between blood
and other remaining compartments of the body.
Elimination- It is defined as the irreversible loss of drug from the body. It
is further divided into two mechanisms such as biotransformation
(metabolism) and excretion.
The process of moving a drug from the bloodstream to tissues is referred to as a
distribution

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FACTORS AFFECTING DISTRIBUTION OF DRUGS
Distribution of drug is the process, which is not uniform throughout the body because of
a number of reasons. The various factors that affect the rate and extent of drug
distribution inside the body are:
1. Membrane permeability which depends on
(i) Physicochemical properties of drugs
(ii) Types and characteristics of various physiological barrBlood perfusion
rate
2. Binding of drug to different component
(i) Binding of drugs to blood
(ii) Binding of drugs to extravascular components
3. Miscellaneous factors
(i) Age
(ii) Pregnancy
(iii) Obesity
(iv) Diseased state
(i) Physiochemical properties of drug: The parameters that effect the distribution of
drug are
Molecular size: Smaller the molecular size of the drug, more easily it crosses the
capillary membrane to enter into the extracellular interstitial fluids. Different
processes are involved in absorption of different molecular size drugs. Those with a
large molecular size undergo endocytosis or facilitated diffusion, while those with
smaller molecular sizes utilize aqueous diffusion or lipid channels.

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Degree of ionization: Different drugs are either acidic or basic and are present in
ionized or unionized form, which is given by their pKa values. In the body, the
ratio of the ionized and unionized forms depends on the pH of the medium.Only
the un-ionized fraction of a drug is available to cross the cell membrane because of
the lipid nature of the membrane. The degree of ionization of a drug in solution
depends on the molecular structure of the drug and the pH of the medium. Most
drugs are weak acids or weak bases and exist in equilibrium of un-ionized and
ionized forms. The variation in the ratio of the two forms with varying pH is given
by the Henderson Hasselbalch equation.
(ii) Types and Characteristics of different Physiological barriers:
A special structure of membrane (barrier) could be the restriction to the permeability or
distribution of drugs to some tissues.
The simple cell membrane barrier
Once the drug diffuses from the capillary wall into the extracellular fluid, then the entry
of drugs into the cells of those tissue which are surrounded by membrane are governed
by the permeability of drugs. One such type of a barrier is the gastro intestinal cells that
are surrounded by the lipoidal barriers which limit the drug absorption.

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Blood-Brain Barrier
The capillary membrane between the plasma and brain cells is much less permeable to
water soluble drugs than is the membrane between plasma and other tissues.
Thus, the transfer of drugs into the brain is regulated by the blood-brain barrier. To gain
access to the brain from the capillary circulation, drugs must pass through cells rather
than between them. Only drugs that have a high lipid-water partition coefficient can
penetrate the tightly opposed capillary endothelial cells.
Blood perfusion rate
The drug distribution is perfusion rate limited when-
• The drug is highly lipophilic.
• The membrane across which the drug is supposed to diffuse is highly permeable
such as those of the capillaries and the muscles.
Perfusion rate is defined as the volume of blood that flows per unit time per unit volume
of the tissue. The rate of blood perfusion to different organs varies widely
Total blood flow is greatest to brain, kidneys, liver, and muscle with highest perfusion
rates to brain, kidney, liver, and heart.

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Organ Perfusion rate (ml/min/ml of tissued)
1. Highly perfused
Lungs 0.02
Kidneys 4.0
Liver 0.8
Heart 0.6
Brain 0.5
2. Moderately perfused
Muscles 0.025
Skin 0.024
3. Poorly perfused
Fat 0.03
Bones 0.02
Binding of drugs to tissue components:
The drug present in the body can interact with several tissue components, which is
divided into
Two categories-
Blood/ Plasma protein
Extra vascular tissue protein
Blood/ Plasma protein
After absorption, the drugs move further either as free drug or bound drug. When the
drugs exist in the free form it is soluble in the plasma and is transported readily but in
bound form the transport becomes limited due to increase size.
The binding of the drug takes place with a variety of proteins present in the plasma like
albumin, globulin, lipoprotein and glycoprotein, etc.
Bound drug is in equilibrium with free drug. Acidic drugs bins to albumin whereas basic
drugs binds to α-acid glycoprotein.
Extra vascular tissue proteins
Tissue-drug binding result in localization of drug at specific site of the body and serves as
reservoir.
A drug needs to bind with a particular tissue or receptor so that a desired therapeutic
response can be observed. In most cases the binding phenomenon is reversible. In case of
irreversible binding of drug results in toxicity issues.

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DRUG METABOLISM
Elimination: The irreversible loss of drug from the body. It is further divided into two
mechanisms
1. Biotransformation or Metabolism
2. Excretion
1. Biotransformation or Metabolism
Metabolism or biotransformation plays a central role in the elimination of drugs and
other foreign compounds from the body.
It may be defined as the chemical alteration of drug by a biological system with principle
purpose of eliminating it from the biological system.
Most of the organic compounds entered into the body are lipophilic in nature, they
absorbed readily, reached to circulation, can diffuse passively through various
membranes and distributed to various organs to show their biological action. Lipophilic
compounds are also absorbed from renal tubules also. Thus, they are not get excreted out
and gets accumulated in the body and causes toxicity. Hence, drug has to undergo
metabolism and converted into more hydrophilic so that it can be easily excreted.
The primary site of drug metabolism is the smooth endoplasmic reticulum of the liver
cell. This is because of the presence of large amounts of many varieties of enzymes. The
drug metabolism happening in the liver is termed as hepatic metabolism. The other sites
include lungs, kidney, placenta, epithelial cells of gastrointestinal tract, adrenals and
skin.
Functional outcomes of drug metabolism
1. Inactivation and accelerated elimination of drugs
2. Activation of prodrugs
3. Formation of active metabolites with similar or novel activity
4. Detoxification of toxic xenobiotics
Major types of drug-metabolizing enzymes
Phase I
• Cytochrome P450 enzymes
• Diaphorase (NADH:quinone oxidoreductase)
Phase II
• UDP-glucuronosyltransferases

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• Sulfotransferases
• Glutathione-S-transferases
• N- and O-acetyltransferases
Drug metabolic process involves two phases
1. Phase I or Non synthetic reactions or Functionalization reactions
2. Phase II or Synthetic reactions or Conjugation reactions
Phase-I or Non synthetic reactions or Functionalization reactions:
In these reactions, a polar group is introduced or unmasked if already present.
Generally these reactions go before phase II reactions including oxidative, reductive and
hydrolytic reactions.
Most of the Phase I products are not eliminated directly; instead they undergo Phase II
reactions.
The principal objectives of these reactions are:
1. Increase in hydrophilicity: a polar functional group is either introduced or
unmasked if already present on the otherwise lipid-soluble substrate. For this
reason, these reactions are also known as functionalization reactions/synthetic
reactions.
2. Reduction in stability: enables reaction with cellular components.
3. Facilitation of conjugation: resultant product from phase I reaction is susceptible
to phase II reactions that make the xenobiotic highly water soluble which can be
easily excreted out of the body.
Oxidation: This is the most commonly occurring reaction, by virtue of which
hydrophilicty of the substrates is increased via the introduction of a polar functional
group such as –OH. This reaction may occur at several centres in drugs, and thus,
oxidation reactions have been classified accordingly.
Oxidation at carbon centre: This includes oxidation at aromatic ring, olefinic centre,
and aliphatic groups. Important drugs undergoing metabolism by this reaction include
acetanilide (analgesic), carbamazepine (antiepileptic) and valproic acid (antiepileptic).

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Oxidation at carbon-heteroatom systems: This involves reaction on C–N, C–S and C–
O systems. The oxidation reactions on C–N systems comprise of N-dealkylation,
oxidative deamination, formation of N-oxide, or N-hydroxylation. The process of
Ndealkylation occurs in the substrates having alkyl group attached directly to nitrogen
atom. Examples include: methamphetamine (antidepressant) which gets metabolized to
amphetamine via Ndealkylation. Amphetamine further gets metabolized to
phenylacetone and ammonia via oxidative deamination.
Reduction: The reduction reactions result in the generation of polar functional groups
such as amino and hydroxyl, which may undergo further metabolic reactions. These
reactions may occur on several functional groups such as carbonyl, hydroxyl, etc.

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Hydrolysis: These reactions generally involve a large chemical change in the substrate.
The hydrolysis reactions can occur in the functional groups like esters, ethers and
amides. Upon hydrolysis, esters lead to the formation of carboxylic acids and alcohols.
Mostly, esters are administered as prodrugs, which on hydrolysis are converted to active
forms, e.g., aspirin (analgesic, antipyretic).
Phase-II or Synthetic reactions or Conjugation reactions
Generally these reactions are covalent attachment of the small polar endogenous
molecules like glucuronic acid, sulphate, glycine, etc to either unchanged drugs or phase
I products having suitable functional groups such as –OH, -COOH, -NH2 and SH to
form highly water-soluble conjugates which are readily removed out by the kidneys.
Therefore, these reactions are also known as Conjugation reactions. As the products of
these reactions are with increased molecular size, these reactions are also known as
synthetic reactions.
Phase-II reaction includes
Glucuronidation: Glucuronidation represents the major route of sugar conjugation.
Mechanistically, glucuronidation is an SN2 reaction in which an acceptor nucleophilic
group on the substrate attacks an electrophilic C-1 atom of the pyranose acid ring of
UDPGA (uridine 5 –diphosphateglucuronic acid) which results in the formation of a
glucuronide, a –D-glucopyranosiduronic acid conjugate.
The transfer of glucuronic acid from UDP- glucuronic acid (UDPGA) is catalysed by a
family of enzymes generally designated as UDP-glucuronosyltransferases (UGTs).

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O
OH O
OH
OH
COO
UDP
H2N
OH
COOH
O
OH
OH
OH
COO
HN
OH
COOH
UDP-Glucuronate p-aminosalicylic acid
UGT
O
OH O
OH
OH
COO
UDP
HO
NHCOCH3
O
OH
OH
OH
COO
O
NHCOCH3
UDP-Glucuronate Acetaminophen
UGT
N-Glucuronidation
O-Glucuronidation

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Acetylation: Acetylation is a Phase II reaction of amino groups and it involves the
transfer of acetyl-coenzyme A (acetyl CoA) to an aromatic primary or aliphatic amine,
amino acid, hydrazine, or sulphonamide group. The primary site of acetylation is the
liver.
Example of N-acetylation reaction is sulphanilamide and isoniazide.
Glutathione Conjugation: Glutathione [N-(N-L-γ-glutamyl-L-cysteinyl)glycine], an
typical tripeptide is an endogenous compound, recognized as playing a protective role
within the body in removal of potentially toxic electrophilic compounds.

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GSH conjugation involves the formation of a thioether link between the GSH and
electrophilic compounds. The reaction can be considered as the result of nucleophilic
attack by GSH on electrophilic carbon atoms, with leaving functional groups such as
halogen, sulphate and nitro, ring opening and the addition to the activated -carbon of an
unsaturated carbonyl compound.
Methylation: O-and N-methylation are common biochemical reactions but appear to be
of greater significance in the metabolism of endogenous compounds than for drugs or
other xenobiotics. However, some drugs may also undergo methylation by non-specific
methyltransferases found in the lung, or by the physiological methyltransferases.
Sulphation: This is a major conjugation pathway for phenols, but also contributes to the
biotransformation of alcohols, amines, and to a lesser extent, thiols.

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Sulphate conjugation is a multistep process, comprising activation of inorganic sulphate,
first, by converting it via ATP to adenosine-5’phosphosulphate (APS), and further to the
activated form, known as PAPS, 3’-phosphoadenosine-5’-phosphosulphate
N
O OH
O
P
N
N
N
H2N
P
O
OO
O
O
OSO
O
O
Overall drug metabolism can be written as shown below:
Oxidation
Reduction
PHASE-I PHASE-II
Electropilic
Nucleophilic
Sulfation
Acetylation
Glucuronidation
Glutathione
conjugationR
R
O R=O
R OH
R NH2
R SH
R GSH
R Glu
R SO3H
R Ac
DRUG
Lipophilic Hydrophilic

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DRUG ELIMINATION
The kidneys and the liver share in the work of getting rid of drugs and their metabolites.
Overview of drug elimination
Very broadly speaking, hydrophilic drug molecules tend to be eliminated via the kidneys
directly, whereas hydrophobic drugs require metabolic transformation in the liver before
undergoing renal or biliary elimination.
Renal excretion = Glomerular filtration + Active tubular secretion – Passive tubular
reabsorption

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Filtration, reuptake and active secretion
Glomerular filtration and active tubular secretion helps in drug excretion from the body
whereas passive tubular reabsorption decreases the drug excretion.

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DRUG TARGETS
Practically all drugs must bind to target molecules in order to exercise their eﬀects. More
than 500 molecular structures were identified that can acts as targets for drug.
Most important drug targets are proteins, nucleic acid, carbohydrates and lipids. Among
them functional classes of protein drug targets are
Receptors
Ion Channels
Carrier molecules
Enzymes
Enzymes as drug targets
These are protein molecules which act as biological catalysts in the body. In their
catalytic activity enzyme performs two important functions.
• An enzyme holds the substrate in its active site in such a way that it can be easily
and effectively attacked by the reagent.
• Enzyme provides functional groups that attack the substrate and carry out
biochemical reactions.
A drug molecule can either increase or decrease the rate of enzyme mediated reactions.
Inducers: An enzyme inducer is a type of drug that increases the metabolic activity of an
enzyme either by binding to the enzyme and activating it.

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Inhibitors: An enzyme inhibitor is a molecule which binds to enzymes and decreases
their activity.
Inhibition of biochemical pathways unique to a pathogen reduce the growth or kill the
pathogen.
Example: Sulfa drugs acts as bacteriostatic by inhibiting dihydropteroate synthatase
enzyme which is required for folic acid synthesis in bacteria.
Types of enzyme inhibition:
1. Non Specific enzyme inhibition
2. Specific enzyme inhibition

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Non Specific enzyme inhibition
A nonspecific inhibition affects all enzymes in the same way. Non-specific methods of
inhibition include any physical or chemical changes which ultimately denature the
protein portion of the enzyme and are therefore irreversible.
Specific enzyme inhibition
Specific Inhibitors exert their effects upon a single enzyme. Most of the poisons and
drugs act by specifically acting on a single enzyme.
Further specific enzyme inhibitors are classified into
i. Reversible inhibition
ii. Irreversible inhibition
Reversible inhibition
Inhibitors can bind to enzyme through weak non covalent interactions such as ionic
bonds, hydrophobic and hydrogen bonds. Reversible inhibitors do not form any
chemical bond or reaction with enzymes. They formed rapidly and can be easily
removed, thus enzyme and inhibitor complex is rapidly dissociated.
Reversible inhibition is classified into three types
i. Competitive inhibition
ii. Non competitive inhibition
iii. Uncompetitive inhibition
Competitive inhibition
A competitive inhibitor is any compound which closely resembles the chemical structure
and molecular geometry of the substrate.
The inhibitor competes for the same active site as the substrate molecule. The inhibitor
may interact with the enzyme at the active site, but no reaction takes place.
However, a competitive inhibition is usually reversible if concentration of substrate
increased.
Therefore, enzyme inhibition depends upon the inhibitor concentration, substrate
concentration and relative affinities of the inhibitor and substrate for the active site.

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E S ES P E
K1
K-1
K2
I
EI
Enzyme-
Inhibitor
complex
Enzyme-
Substrate
complex
The result will be decrease in Vmax and increase in Km.
1 / [S]
1 / V
-1 / Km'-1 / Km
Competitive inhibitor
No inhibitor
Example: Ethanol is metabolized in the body by oxidation to acetaldehyde, which is in
turn further oxidized to acetic acid by aldehyde oxidase enzymes. Normally, the second
reaction is rapid so that acetaldehyde does not accumulate in the body. A drug,
disulfiram (Antabuse) inhibits the aldehyde oxidase which causes the accumulation of
acetaldehyde with subsequent unpleasant side effects of nausea and vomiting. This drug
is sometimes used to help people overcome the drinking habit.

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Michaelis-Menten equation:
Vo = Vmax [S] / Km + [S]
If Km is high, the affinity of the enzyme is low and
If Km is low, the affinity of the enzyme is high.
Vmax cannot be easily determined from the graph as the exact point wherein the curve
turns parallel to the X-axis is difficult to determine. Hence a linear plot would be easier
to analyse. Hans Lineweaver and Dean Burk used the Michaelis–Menten equation and
converted it into a double reciprocal format as follows-
Vo = Vmax [S] / Km + [S]
taking reciprocal on both sides
1 / Vo = Km / Vmax [S] + 1 / [S]
Non competitive enzyme inhibitor
The inhibitor may bind to both free enzyme and the enzyme substrate complex. The
affinity of the inhibitor to the two complexes could be different.
The inhibitor can bind to the enzyme at the same time as the enzyme's substrate.
However, the binding of the inhibitor affects the binding of the substrate, and vice versa.
This type of inhibition can be reduced, but not overcome by increasing concentrations of
substrate. If binding of inhibitor changes the affinity for the substrate, Km will be changed
called mixed inhibition.
This type of inhibition generally results from an allosteric effect where the inhibitor binds
to a different site on an enzyme. Inhibitor binding to this allosteric site changes
the conformation (i.e., tertiary structure or three-dimensional shape) of the enzyme so
that the affinity of the substrate for the active site is reduced.
The binding of the inhibitor to the enzyme reduces its activity but does not affect the
binding of substrate. As a result, the extent of inhibition depends only on the
concentration of the inhibitor. Vmax will decrease due to the inability for the reaction to
proceed as efficiently, but Km will remain the same as the actual binding of the substrate
it is non competitive inhibition.

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The result will be decrease in Vmax and increase or decrease in Km value. The effect can
only be partially overcome by high substrate concentration.
E S ES P E
K1
K-1
K2
I
EI
Enzyme-
Inhibitor
complex
Enzyme-
Inhibitor-
Substrate
complex
I
EIS
Ki Ki'
Linewaver-Burk plot for mixed inhibition i.e. both Vmax and Km values are changed..
1 / [S]
1 / V
-1 / Km'-1 / Km
Mixed inhibition
No inhibitor

UNIT-III
Linewaver-Burk plot for non competitive inhibition i.e. only Vmax value changed and Km
values remain same.
Uncompetitive enzyme inhibition
The inhibitor binds only to the substrate-enzyme complex. This type of inhibition
causes Vmax to decrease (maximum velocity decreases as a result of removing activated
complex) and Km to decrease.
E S ES P E
K1
K-1
K2
Enzyme-
Inhibitor-
Substrate
complex
I
EIS
Ki'
1 / [S]
1 / V
-1 / Km
Non competitive
inhibition
No inhibitor

UNIT-III
Effect cannot be minimized by high substrate concentration i.e. increasing the substrate
concentration favours the inhibition by inhibitor.
1 / [S]
1 / V
-1 / Km'
Uncompetitive
inhibition
No inhibitor
-1 / Km
Irreversible enzyme inhibition
Inhibitor generally makes a covalent bond with one of the amino acid residue within the
enzyme and this then reacts to produce the covalently modified "dead-end complex" EI*
(an irreversible covalent complex). The rate at which EI* is formed is called the
inactivation rate or Kinact.
E S ES P E
K1
K-1
K2
I
EIS
Ki'
I
EI
Ki
EI*

UNIT-III
Affinity labels
These bear structural similarity to the regular substrate that when enzyme binds to them,
an active functional group on the inhibitor interacts covalently with nearby amino acid
group there by inhibiting the enzyme.
Nerve gases like diisopropyl fluorophosphate, DIPF, irreversibly inhibit nerve action by
forming covalent bonds to the OH group of serine on the active site of the enzyme
acetylcholinesterase.
Suicide Substrate
Also known as mechanism based inhibition, these molecule are substrate analogs that
bind to the active site and initiates catalytic process. However, during the reaction a
reactive intermediate is formed that modifies the residue on the active site covalently
there by inhibiting the enzyme.
Aspirin inhibits COX enzyme by acetylating the hydroxyl of a serine.

UNIT-III
Michaelis-Menten kinetic equation used extensively in studying enzyme kinetics based
on single substrate reactions, more than 60 % of all enzyme catalysed reactions are
bisubstrate in nature.
A special nomenclature and representation of bisubstrate was proposed by W.W.
Cleland.
1. Substrates are introduced as A, B, C, D in the order they bind to enzyme.
2. Products are called P, Q, R and S in the order they leave the enzyme.
3. Uni (one), Bi (two), Ter (three) and Quad (four) are used to describe the number
of substrates and products involved in that order.
For example following reaction has two substrates and two products. Hence it is called a
Bi-Bi reaction.
A B P Q
Bi-Bi reaction fall into two categories
1. Sequential or single displacement reactions
Here the two substrates A and B must bind first in ordered manner or randomly to the
enzyme followed by the release of the products P and Q again in an ordered manner or
randomly. Because the two substrates must first bind before the two products are
released, hence the terminology- single displacement.
2. Double displacement or Ping Pong reactions
In some Bi Bi reactions a substrate (called leading substrate) first binds to the enzyme
followed by the release of the leading product. Then the second substrate is bound

UNIT-III
following which a second product is released. Because this mechanism resembles a to
and fro movement of the ball in a ping-pong ortable tennis game, the mechanism is
popularily called Ping-Pong. Two displacements reactions are involved and hence they
are also known as double displacement reactions.
Rate equations and double reciprocal plots
For determining the rate of bisubstrate reactions of the type-
A B P Q
One of the substrates say B is kept constant and the concentration of A is varied and a
plot of 1/Vo vs 1/[A] is made (Lineweaver-Burk plot). In another set of reactions the
concentration of A is kept constant and the concentration of B is varied. Again a plot of

UNIT-III
For a double displacement /Ping Pong type Bi Bi reaction the steady state kinetic
equation is given below and the double reciprocal plot is as follows

UNIT-III
Receptors as drug targets
Receptors are specific areas of cell membranes (protein, glycoproteins) when bound to a
ligand initiates the chain of biochemical reactions that leads to positive or negative
biological response.
OR
The site of drug action which is ultimately responsible for the pharmaceutical effect is a
receptor.
Receptors has two main functions
• Ligand binding (Affinity)
• Generating effectors response (Efficacy)
Differences between enzymes and receptors
Enzyme Substrate Product
Receptor Ligand Response
Similarities between enzymes and receptors
• Inertness: Bothe by themselves inert and can produce an effect only in presence
of a substrate or ligand.
• Targets: Both can acts as targets for drug molecules.

UNIT-III
• Reaction Kinetics: Both functions can be described by kinetic equation like rate
of association and dissociation. As long as enzyme is bound to substrate there is
product formation and when substrate dissociates from enzyme product is
formed. Similarly, as long as ligand bound to receptor, there is response. When
ligand dissociates there is no further response.
• Competitors: Their action can be controlled by competitors for binding i.e. a
substrate binds to enzyme and ligand that binds to receptor can be displaced by a
competitor.
• Inhibitors: Function of enzyme and receptor can be blocked or inhibited by
respective inhibitors.
Receptor types
There are two types of receptors. These are
1. Intracellular or Internal or Cytoplasmic receptor- found in cytoplasm or nucleus
and responds to hydrophobic ligand molecules.
2. Cell surface receptor-found on the surface of plasma membrane and performs
signal transduction by converting an extracellular signal into an intracellular
signal.
There are three general categories of cell surface receptors:
1. Ion channel linked receptors (Ionotropic)
2. G-Protein coupled receptor (Metabotropic)
3. Enzyme linked receptor

UNIT-III
For each type of receptor, there is a specific group of drugs or endogenous substances
known as ligands that are capable of binding to the receptor and producing a
pharmacological effect.
There are four types of ligands that act by binding to cell surface receptor
1. Agonist
2. Antagonists
3. Partial agonist
4. Inverse agonist
Agonist
A drug that activates a receptor is known as Agonist.
Agonists can differ in both affinity and efficacy for receptor. Based on this there are three
types.
1. Full agonist – have affinity and maximal efficacy
2. Partial agonist – have affinity but low efficacy
3. Inverse agonist – binds to active receptor, stabilize them and reduce the activity.
Produced effect is specifically opposite to that produced by agonists.

UNIT-III
Antagonist
A drug that does not activates the receptor, but binds to the receptors. Prevent the
natural agonist from exerting its effect by binding to the same active site without
showing any activity.
Two types of antagonists are
1. Competitive antagonist: binds to the same binding site as that of agonist and
competes with the agonist for the same binding site. The effect can be overcome
by increase of drug (agonist) concentration.
2. Non competitive antagonist: have different binding site and therefore do not
compete with the agonists.
Ion channel linked receptors (Ionotropic)
These are protein pores that open or close n response to a chemical signal. This allows or
blocks ion flow such as Na+
or Ca2+
through a channel in the receptor. Binding of
receptor by a ligand to the extracellular side changes the proteins shape and open the
channel. Ion flow changes the concentration inside the cell. When the ligand dissociates,
the channel closes.
Example Acetylcholine binds to acetylcholine receptor on a Na+
channel, channel opens
and allows Na+
ion to enter inside the cell.

UNIT-III
G-Protein coupled receptor (Metabotropic)
G-protein coupled receptors are involved in responses of cells to many different kinds of
signals, from epinephrine, to odors, to light. In fact, a variety of physiological
phenomena including vision, taste, smell and the fight-or-flight response are mediated by
GPCRs.
G-protein is a guanine nucleotide-binding protein that can interact with a G-protein
linked receptor. There are many different G-proteins they are composed of three subunits
called alpha, beta and gamma.
Enzyme linked receptor
Enzyme-linked receptors are a group of multi-subunit transmembrane proteins that
possess either intrinsic enzymatic activity in their intracellular domain or associate
directly with an intracellular enzyme

UNIT-III
Groups of receptors that have intrinsic enzymatic activities include:
(1) Receptor Tyrosine Kinases (RTK) (e.g. PDGF, insulin, EGF, VEGF and FGF
receptors).
(2) Receptor Tyrosine Phosphatases (e.g. CD45 [cluster determinant-45] protein of T
cells and macrophages).
(3) Receptor Guanylate Cyclases (e.g. natriuretic peptide receptors).
(4) Receptor Serine/Threonine Kinases (e.g. activin and TGF-β receptors).
(5) Tyrosine-Kinase Associated Receptors: Receptors that associate with proteins that
have tyrosine kinase activity (Cytokine Receptors, T- and B cell receptors, Fc receptors)
Receptor Tyrosine Kinases (RTK)
The predominant type of enzyme-linked receptors is family of the tyrosine kinase
receptors, also referred to as receptor tyrosine kinases. Tyrosine kinases are signaling
proteins with catalytic activity to phosphorylate tyrosine residues. There are two major
groups of tyrosine kinases:
(1) “Complete” Receptor tyrosine kinases (RTK) are cell surface receptors with intrinsic
kinase activity (i.e. own intracellular kinase domain) [e.g. growth factor receptors].
(2) “Incomplete” or Non-receptor tyrosine kinases (nRTK) are cytosolic or membrane-
anchored kinases associated with different cell surface receptors and transmit their signal
towards the intracellular signaling networks [e.g. Src family kinases, Syk family kinases].
Main steps of RTK signaling
1) Ligand binding to RTK monomers results in dimer formation.
2) Within the dimer the conformation is changed, locking the kinase into an active
state
3) The kinase of one receptor then phosphorylates a tyrosine residue contained in
the "activation lip" of the second receptor.
4) This forces the activation lip out of the kinase active site, allowing ATP bind and
resulting in enhanced kinase activity. This induces phosphorylation at further
tyrosine residues.
5) Phosphotyrosine is a conserved "docking site" for many intracellular signal
transduction proteins that contain SH2 domains.

UNIT-III
For example, upon binding to RTKs, surface proteins called ephrins help guide
developmental processes involved in tissue architecture, final placement of nerve
endings, and blood vessel maturation.
When RTKs don't function properly, cell growth and differentiation go awry. For
instance, many cancers appear to involve mutations in RTKs. For this reason, RTKs are
the targets of various drugs used in cancer chemotherapy. For example, the breast cancer
drug Herceptin is an antibody that binds to and inhibits ErbB-2 — an RTK that is over
expressed in many metastatic breast cancers.
Internal or Cytoplasmic receptor
Lipophilic ligands enter the cell and then bind and activate a recptor in the cytoplasm or
nucleus. The activated receptor complex regulates transcription and therefore protein
synthesis. Very slow response.

UNIT-III
Drug-Receptor interaction
Drugs interact with receptors in a reversible manner to produce a change in the state of
the receptor, which is then translated into a physiological effect.
The driving force for the drug-receptor interaction can be considered as a low energy
state of the drug receptor complex.
ReceptorDrug Drug-Response Complex
K1
K-1
Response
K2
This molecular interaction with the receptor can be modelled mathematically and obeys
the Law of Mass Action.
Kd =
[DR]
[D] [R]
Kd = Dissociation constant for the drug-receptor complex at equilibrium
The binding of drug and receptor determines the quantitative relationship between dose
and effect.

UNIT-III
Theories of Drug-Receptor interactions
1. Occupancy theory
2. Rate theory
3. Induced fit theory
4. Macromolecular perturbation theory
5. Activation aggregation theory
Occupancy theory
Intensity of the pharmacological effect is directly proportional to the number of receptors
occupied by the drug.
A RA-R
Response is proportional to the fraction of occupied receptors. Maximal response occurs
when all the receptors are occupied.
Response = FRbound
[AR]
[R]0
=
FRbound = Fraction of receptor bound
Rate theory
Paton in 1961 proposed that the response is proportional to the rate of drug-receptor
complex formation rather than number of receptors occupied by the drug.
Activation of receptors is proportional to the total number of encounters of a drug with
its receptor per unit time.
Induced fit theory
A specific conformational change in a receptor is responsible for initiation of the
biological response. Agonist bonding induces this conformational change.
Partial agonist induces partial conformational change hence there will be partial
response.
Antagonist does not induce conformational change hence there is no response.
Macromolecular perturbation theory
When a drug receptor interaction occurs, one of two general types of macromolecular
perturbation is possible i.e.
• A specific conformational perturbation leads to a biological response (Agonist).

UNIT-III
• A non specific conformational perturbation leads to no biological response
(Antagonist).

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