Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial

ASBASJSM COLLEGE OF PHARMACY (AN AUTONOMOUS COLLEGE) BELA

COLLEGE OF PHARMACY
(An Autonomous College)
BELA (Ropar) Punjab

Name of Unit General Pharmacology

Subject /Course name Pharmacology-I
Subject/Course ID BP404T
Class: B.Pharm. Semester IV
Course coordinator Devinder Kumar
Mobile No. 8219193104
Email id [email protected]

Learning Outcome of Module-2

LO Learning Outcome Course Outcome

Code
LO1 To Understand the principles and mechanism of drug action BP404.2
LO2 To Understand the receptor theories &receptors classification. BP404.2
LO3 To Understand the dose response relationship, therapeutic BP404.2
index and factor modifying drug action drug action.
LO4 To understand the Adverse drug reactions and Drug BP404.2
Interactions
LO5 To Understand the Drug discovery and Clinical evaluation of BP404.2
new drug, Pharmacolvigilance

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Content Table
Topic
 Pharmacodynamics- principles and mechanisms of drug action.
 Receptor theories and classification of receptors, regulation of receptors.
 Drug receptors interactions signal transduction mechanisms,
 G-protein-coupled receptors, ion channel receptor, transmembrane enzyme linked
receptors,
 Transmembrane JAK-STAT binding receptor and receptors that regulate transcription
factors.
 Dose response relationship, therapeutic index.
 Combined effects of drugs and factors modifying drug action.
 Adverse drug reactions, drug interactions.
 Drug discovery and clinical evaluation of new drugs -drug discovery phase, preclinical
evaluation phase, clinical trial phase, phases of clinical trials.
 Pharmacolvigilance.

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PHARMACODYNAMIC
Pharmacodynamic- Pharmacodynamic is a study of drug’s effect on body, so we can say it’s
a study of- what does DRUG do to the BODY.
Pharmaco Dynamics- What does DRUG 1do to the BODY2. Means is Drug is in the first line. (D
of Dynamic and D of Drug is in continues mode)
Pharmacodynamics is concerned with the study of the mechanism of drug and pharmacological
effect produced on the body. The drugs administered are not having effectiveness only but they
have also adverse effect side effect and toxicity.
The drug used for the treatment should be of maximum effectiveness and with minimum toxicity
and side effect.
Action of drug: it is the process by which the drug or chemical substance induce change in pre-
existing physiological function of living organisms.
Effect of drug: The series of changes occurs after drug action is called effect of drug,
Ex. In case of fever, the body trmprature is elveted (increased) above normal body temperature.
Tablet Acetaminophen (Paracetamol) is antipyretic the drug administered, it disintegrates, absorb
then act on heat regulating center. It lowersthe raised body temperature to normal body
temperature.

Principles of Drug Action

Drugs (except those gene based) do not impart new functions to any system, organ or cell; they
only alter the pace of ongoing activity. However, this alone can have profound medicinal as well
as toxicological impact. The basic types of drug action can be broadly classed as:
Irritation- There is few drugs which irritate the site of action and produce there effect. Example-
Senna and some other drug used in constipation irritate the intestine and increase defecation.
Other balm in case of headache will irritate the forehead tissue and gives relief from pain for short
duration.
Stimulation- Stimulation means to increase the function of any specialized organ, which will
result in extra work, like in case of fear or fight adrenaline is gets secreted and heart rate increase
which give FFF (Fight-Flight-Freeze response).
Depression- The simple meaning of depression is the reduction of specialized activity. For
example- Barbiturate and benzodiazepine depress the CNS and give depression action. As same
Omeprazole reduce gastric acid secretion.
Replacement- When any hormone or biochemical substance is in inadequate quantity and there
recovery is not possible then there is one option of replacement. The replacement is done for

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insulin in case of insulin dependent diabetes; here insulin is given by injection to maintain the
requirement
Cytotoxic- When there is entry of any parasite, or there is no other option to control the growth of
own body cell then Cytotoxic drugs are used. They kill the microorganism of kill the uncontrolled
and excessive growing cells.

Mechanism of Drug Action

Only a handful of drugs act by virtue of their simple physical or chemical property; examples are:
• Bulk laxatives (ispaghula)—physical mass
• Dimethicone, petroleum jelly—physical form, opacity
• Para amino benzoic acid—absorption of UV rays
• Activated charcoal—adsorptive property
• Mannitol, mag. sulfate—osmotic activity
• 131I and other radioisotopes—radioactivity
• Antacids—neutralization of gastric HCl
• Pot. Permanganate—oxidizing property
• Chelating agents (EDTA, dimercaprol)—chelation of heavy metals.
• Cholestyramine—sequestration of bile acids and cholesterol in the gut
• Mesna—scavenging of vasicotoxic reactive metabolites of cyclophosphamide
Majority of drugs produce their effects by interacting with a discrete target biomolecule, which
usually is a protein. Such mechanism confers selectivity of action to the drug
Functional proteins that are targets of drug action can be grouped into four major
categories, viz.
 Enzymes
 Ion channels
 Transporters
 Receptors

ENZYMES
Almost all biological reactions are carried out under catalytic influence of enzymes. Drug can
either increase or decrease the rate of enzymatically mediated reactions
Enzyme Inhibition:
Selective inhibition of particular enzyme is common mode of action. Such inhibit on is either
competitive or non-competitive.

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Competitive Inhibitions:
When the active site or catalytic site of an enzyme is occupied by the substance other than the
substrate of that enzyme. Its activity is inhibited. This type of inhibition is also known
competitive inhibition.

In such inhibition both ES and ET complex are formed during their reaction. With the increase in
conc. Of inhibitors, lowers the rate of enzymatic reaction, Such inhibitors increase the kM but the
Vmax remains unchanged. However when the concentration of substrate is increased the effect of
inhibitor can be reversed forcing it out from EI complex.

Non-Competitive Inhibitions:
These are not influenced by the concentration of the substrate of inhibits by binding irreversibly
to the enzyme but not at the active site.
They also bind with same affinity to the free enzyme and form the enzyme substrate complex
It changes the shape of enzyme and active site

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Uncompetitive Inhibitions:
Uncompetitive inhibitors do not bind to the free enzyme. They bind only to the enzyme substrate
complex to yield inactive ESI complex.
Uncompetitive inhibitors frequently observed in multimutated reaction. Inhibition can‘t be
reversed by increasing the Since I doesn‘t compete with s from the same binding site.

ION CHANNELS:
Ion channels are pore forming membrane proteins that allow ions to pass through the channel
pore.
Their functions include establishing a resting membrane potential shaping action potentials and
other electrical signals by gating the flow of ions across the cell membrane.
The rate of ion transport through the channel is very high.
Ions pass through channels down their electrochemical gradient which function of ion
concentration and membrane potential ―Downhill‘‘ without the input of metabolic energy.
e.g Adenosine Triphosphate, active transport mechanism.

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They are operated by specific signal molecules either directly and are called ligand gated
channels (e.g. nicotinic receptor,) or through G-proteins and are termed G-protein regulated
channels (e.g. cardiac adrenergic receptor activated Ca2+ channel. Drugs can also act on voltage
operated and stretch sensitive channels by directly binding to the channel and affecting ion
movement through it, e.g. local anesthetics which obstruct voltage sensitive Na+ channels.
Quinidine blocks myocardial Na+ channels.
Dofetilide and amiodarone block myocardial delayed rectifier K+ channel.
Nifedipine blocks L-type of voltage sensitive Ca2+ channel.
Nicorandil opens ATP-sensitive K+ channels.
Sulfonylurea hypoglycaemics inhibit pancreatic ATP-sensitive K+ channels.
Amiloride inhibits renal epithelial Na+ channels.
Phenytoin modulates (prolongs the inactivated state of) voltage sensitive neuronal
Na+channel.
Ethosuximide inhibits T-type of Ca2+ channels in thalamic neurons

TRANSPORTERS:
Several substrates are translocate across membranes by binding to specific transporters (carriers)
which either facilitate diffusion in the direction of the concentration gradient or pump the
metabolite/ion against the concentration gradient using metabolic energy. Many drugs produce
their action by directly interacting with the solute carrier (SLC) class of transporter proteins to
inhibit the ongoing physiological transport of the metabolite/ion.
Ex: Desipramine and cocaine block neuronal reuptake of noradrenaline by interacting with
norepinephrine transporter . Fluoxetine (and SSRIs) inhibit neuronal reuptake of 5-HT by
interacting with serotonin transporter (SERT).

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RECEPTORS
It is defined as a macromolecule or binding site located on the surface or inside the effector cell
that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no
other function.
OR
Receptors are macromolecules involved in chemical signaling between & with in the cells. They
may be located on the cell surface membrane or within cytoplasm.
The largest number of drug that do not bind directly to the effectors like Enzyme, Channels,
Transport structural protein, template biomolecule. But act through specific regulatory
macromolecules or the site which bind and interact with the drug are called ―Receptor‖

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Following terms related to receptor and drug receptor complex

Agonist: An agent which activates a receptor to produce an effect similar to that of the
physiological signal molecule.
Antagonist: An agent which prevents the action of an agonist on a receptor or the subsequent
response, but does not have any effect of its own.
Partial agonist: An agent which activates a receptor to produce submaximal effect but
antagonizes the action of a full agonist.

Inverse agonist: An agent which activates a receptor to produce an effect in the opposite
direction to that of the agonist.

Ligand: (Latin: ligare —to bind) - Any molecule which attaches selectively to particular
receptors or sites. The term only indicates affinity or ability to bind without regard to functional
change: agonists and competitive antagonists are both ligands of the same receptor.

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RECEPTOR THEORIES
RECEPTORS – A receptor is the specific chemical constituent 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.
The term drug receptor or drug target denotes the cellular macromolecule or macromolecular
complex with which the drug interacts to elicit a cellular response, i.e., a change in cell function.
D+R D-R Drug Response
A Receptor is analogous to a switch that it has two configurations: ―ON‖ and ―OFF‖
Receptor: Any cellular macromolecule that a drug binds to initiate its effects.
Drug: A chemical substance that interacts with a biological system to produce a physiologic
effect. All drugs are chemicals but not all chemicals are drugs.
The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to
interact with complementary surfaces on the receptor.
Once bound to the receptor an agonist activates or enhances cellular activity.
Examples of agonist action are drugs that bind to beta receptors in the heart and increase the force
of myocardia contraction or drugs that bind to alpha receptors on blood vessels to increase blood
pressure. The binding of the agonist often triggers a series of biochemical events that ultimately
leads to the alteration in function.

THEORIES FOR DRUG RECEPTOR INTERACTION

Over the years a number of hypotheses have been proposed to account for the ability of a drug to
interact with a receptor and elicit a biological response. Several of the more important proposals
are:
OCCUPATION THEORY
The occupancy theory of Gaddum and Clark states that the intensity of the pharmacological effect
is directly proportional to the number of receptors occupied by the drug.
Maximal response occurs when all the receptors are occupied.
D + R ↔ DR⇒ RESPONSE
The concept of drug–receptor interactions involve two stages: first, there is a complexation of the
drug with the receptor, which termed the affinity; second, there is an initiation of a biological
effect, which termed the intrinsic activity and the efficacy.
Affinity is a measure of the capacity of a drug to bind to the receptor.
Intrinsic activity (α) or Efficacy is the property of a compound that produces the maximum
response or the ability of the drug– receptor complex to initiate a response.

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THE TWO-STATE (MULTISTATE) MODEL OF RECEPTOR ACTIVATION

It was developed on the basis of the kinetics of competitive and allosteric inhibition as well as
through interpretation of the results of direct binding experiments.
It postulates that a receptor, regardless of the presence or absence of a ligand, exists in two
distinct states: the R (relaxed, active or on) and T (Tense, inactive or off) states, which are in
equilibrium with each other. In the absence of the natural ligand or agonist, receptors exist in
equilibrium (defined by equilibrium constant L; Figure 4) between an active state (R*), which is
able to initiate a biological response, and a resting state (R), which cannot.
In the absence of a natural ligand or agonist, the equilibrium between R* and R defines the basal
activity of the receptor.
A drug can bind to one or both of these conformational states, according to equilibrium constants
Kd and K*d for formation of the drug– receptor complex with the resting (D•R) and active
(D•R*) states, respectively.

D R D R*

Resting Active

Kd K d*

D. R D.R**

Full agonists bind only to R*

Partial agonists bind preferentially to R*
Full inverse agonists bind only to R
Partial inverse agonists bind preferentially to R
Antagonists have equal affinities for both R and R* (no effect on basal activity)

RATE THEORY
The response is proportional to the rate of drug-Receptor complex formation.
Effect is produced by the drug molecules based on the rates of association and dissociation of
drugs to and from the receptors.
As an alternative to the occupancy theory, Paton proposed that the activation of receptors is

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proportional to the total number of encounters of the drug with its receptor per unit time.
Therefore, the rate theory suggests that the pharmacological activity is a function of the rate
of association and dissociation of the drug with the receptor and not the number of occupied
receptors. Each association would produce a quantum of stimulus.
In the case of agonists, the rates of both association and dissociation would be fast.
The rate of association of an antagonist with a receptor would be fast, but the dissociation
would be slow.
Partial agonists would have intermediate drug–receptor complex dissociation rates.

INDUCED-FIT THEORY
The induced-fit theory of Koshland was originally proposed for the action of substrates with
enzymes, but it could apply to drug–receptor interactions as well.
According to this theory, the receptor need not necessarily exist in the appropriate
conformation required to bind the drug.
As the drug approaches the receptor, a conformational change is induced, which orients the
essential binding sites.
The conformational change in the receptor could be responsible for the initiation of the
biological response (movement of residues to interact with the substrate).
The receptor (enzyme) was suggested to be elastic, and could return to its original
conformation after the drug (product) was released.
The conformational change need not occur only in the receptor (enzyme), the drug (substrate)
also could undergo deformation, even if this resulted in strain in the drug (substrate).
According to this theory, an agonist would induce a conformational change and elicit a
response, an antagonist would bind without a conformational change, and a partial agonist
would cause a partial conformational change.
The induced- fit theory can be adapted to the rate theory. An agonist would induce a
conformational change in the receptor, resulting in a conformation to which the agonist binds
less tightly and from which it can dissociate more easily.
If drug–receptor complexation does not cause a conformational change in the receptor, then
the drug–receptor complex will be stable, and an antagonist will result.

MACROMOLECULAR PERTURBATION THEORY

Having considered the conformational flexibility of receptors, Belleau suggested that in the
interaction of a drug with a receptor two general types of macromolecular perturbations

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could result:
A specific conformational perturbation makes possible the binding of certain molecules that
produce a biological response (an agonist).
A non- specific conformational perturbation accommodates other types of molecules that do
not elicit a response (e.g., an antagonist).
If the drug contributes to both macromolecular perturbations, a mixture of two complexes
will result.
This theory offers a physicochemical basis for the rationalization of molecular phenomena
that involve receptors, but does not address the concept of inverse agonism

CLASIFICATION OF RECEPTORS
Receptor is a membrane bound or soluble proteins or proteins complex which exerts a
physiological effect after binding its natural ligand. The drugs can acts though various types of
receptors with their signal Transduction Mechanism,
The receptors are classified on the basis of nature of receptor and regulate path

TRANSDUCTION MECHANISM
 G protein- coupled receptors
 Enzyme linked receptor
 Voltage dependent ion channels
 Other member receptors
 Nuclear receptors

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G - Protein- Coupled Receptors (GPCRs)

GPCRS are the largest family of membrane proteins and mediate most cellular responses to
hormones and neurotransmitters, as well as responsible for vision, olfaction and taste.
GPCRS are characterized by the presence of seven membrane spanning alpha helical
segments separated by alternating intra and extracellular loop regions.
If agonist and antagonist bind to Gpcr iI cause the receptor and g-protein change
conformation.
The alpha subunits exchange the guanosine triphosphate (GTP) for guanosine diiphosphate
(GDP) and dissociates from the other subunits, where it interacts with an effectors proteins
(adenylate cyclase and phospholipase c)
This effector protein can stimulate or inhibit second massager molecules to produce a
physiological effect.
The alpha subunit then hydrolysis the bound GTP to GDP and reassociates with the other
subunits.
 Gs protein activate cAMP
 Gi proteins inhibit cAMP
 Gq protein activate phospholipase C, which increase DAG and IP3
When G protein is activated, GTP replaced GDP on the alpha subunit. Following activation of
Protein, GTP is rapidly degraded to inactive GDP by Activte of the alpha subunit GTPase

G. protein couple receptor regulates through Adenylyl cyclase: cAMP pathway

Agonist or ligand bind to GPCR that activate Gs stimulate Adenylate cyclase to convert ATP to
the cAMP Cyclic adenosine monophosphate.

G PCR, action through Adenylate cyclase system. Stimulation/Inhibition depend upon nature of agonist
and antagonist

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Then cAMP Activate Second massager of Protein kinase A which phosphorylated the protein,
resulting in alter the function of many enzymes, ion channel, carrier and structural proteins to
results as increased contraction, relaxation on smooth muscle, glycogenolysis, lipolysis etc. When
the ligand bind to GPCR than Activates Gi inhibit adenylate cyclase (↓CAMP) Therefore protein
kinase A is not activated and proteins are note phosphorylated. It is opposite process activation.
G. protein couple receptor regulates through Phospholipase C- IPS-DAG Pathway
Activation of phospholipase C by the activated GTP carrying ά subunits of Gq hydrolyses
the membrane phospholipids inositol 4,5 bisphosphate to generate the second messenger
inositol 1,4,5 triphosphate (IP3)and diacylglycerol (DAG)
The IP3 being water soluble diffuse to the cytosol and mobilize Ca2+ from endoplasmic
reticulum depot.
The lipophilic DAG remains within the membrane but recruits protein kinase and
activate it with the help of Ca2+
The activated protein kinase phosphorylates many intra cellular proteins and mediates
various physiological responses. That‘s why it serve in signaling function.
The cytosolic concentration of Ca2+ is kept very low (About l00nM) by specific pumps
located at plasma membrane and at the endoplasmic reticulum.
Triggering by IP3 the released Ca2+ (3rd Messenger) act as highly versatile regulator
acting through calmodulin.

GPCR regulate through IP3DAG pathway.

Agonist shows stimulation action and antagonist shows inhibition action

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Ligand Gated Ion Channels

It is made up of five multi subunit proteins (2ά,β,γ and δ)
It is a large group of intrinsic transmembrane proteins that allow the passage of ion upon
activation by specific chemical.
Most endogenous ligand bond to distinct from the ion conduction pore and binding directly
causes opening or closing of the chemical.
Ligand can bind extracellular eg Glutamate, ACH and GABA or intracellular Ca2+ on Ca2+
activated K+ channels.
It is important to note that the ligand itself is not transported across cell membrane.

Diagram represented the ligand gated ion channel

Ligand binding causes a drastic change in the permeability of the channels to a specific ion or
ions; effectively no ions can pass through the channel when it is inactive but to 107 ions per
second can allow trough upon ligand binding.
This ligand gated ion channel, a type of ion tropic receptor, allows specific ions (like Na+ K+
Ca2+ and Cl-) to flow in and out of the membrane.
Examples of ligand gated ion channels include ach receptors , serotonin, GABAA and
Glutamate receptor.

Voltage Dependent Ion Channels

Voltage dependent ion channels are a class of transmembrane proteins that form ion channel
that are activated by change in the electrical membrane potential near the channel.
The membrane potential alters the confirmation of the channel positive proteins, regulating
their opening and closing.
It is normally open or close in response to changes in the membrane potential, but they can
also function receptors for drugs.

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Example: The Calcium channel blockers bind to voltage-dependent Ca2+/Na2+ channels and
block Ca2+,Na2+ entry into the cells when stimulated . This cause decreased contractility in
target tissues, such as cardiac and smooth muscle.

A systematic diagram of movement of ions and their effects

Transmembrane Enzyme-linked receptor
It is the class of receptor themselves is enzymatic proteins. When a drug binds to this type
receptor, it causes an enzyme to become ―switched on‖ intercelluarly.
This enzyme then catalyzes the formation of other signal proteins that ultimately lead to the
cellular response. Some peptide hormones and cytokines act through this class of receptors.
The enzyme in most cases is a tyrosine proteins kinase.

Enzyme Linked insulin receptors

Eg. Insulin bind to the tyrosine kinase receptor cause the enzyme to phosphorylate tyrosine
residues in proteins. The proteins can then signal other proteins to be formed resulting in glucose
uptake.

Transmembrane JAK-STAT binding

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The Tyrosine kinase activity of JAK is activated when the regulatory molecule binds and
brings two receptor molecules together to form a dimer.
Receptor dimerization brings the two JAKs into close proximity where they can
phosphorylate each other.
Phosphorylation further activates JAK allowing it to phosphorylate the receptor.
The phosphotyrosine residues on the receptor proteins are binding sites for STAT proteins.
STAT stands for Signal Transducer and Activator of Transcription.
The STAT proteins are considered latent transcription factor. Latent means that they are
always present in the cytoplasm and waiting to be activated by JAK.
When STAT bind to receptor, that brings it into position where it can phosphorylated by JAK.
Once phosphorylated, Two STATs can then form STAT dimer. The STAT dimer is in active
transcription factor.

Systematic diagram of transmembrane receptor tyrosine kinase activity of JK

It travels nucleus where it binds to specific sequences in the DNA. Inactivation occurs when
phosphatases remove phosphate groups from various proteins in the signaling pathway.
Other member receptor
Integrin is obligate heterodimers, means they have two subunits; alpha and beta.
Integrin‘s in mammals have twenty four alpha and nine beta subunits.
Integrin‘s are transmembrane receptors that facilitate cell-extracellular matrix (ECM)
adhesion. Upon ligand binding, integrin‘s activate signal transduction pathways that mediate
cellular signals such as regulation of cell cycle, an organization of the intracellular
cytoskeleton, and movement of new receptors to the cell membrane.
The presence of integrin allows rapid and flexible responses to events at the cell membrane.
The presences of integrin allow rapid and flexible responses to events at the cell surface.

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Nuclear Receptor
The lipid-soluble drugs diffuse through cell membrane and bind either in the cellular cytosol
or in the nucleus.
Gene expression is altered, and protein synthesis is either increased or decreased, which
causes the cellular response.
This mechanism is the slowest and effects can usually be measured in term of hours rather
than minutes or seconds.

Nuclear Receptor
Various drug acts through nuclear receptor. Lipophilic substances, such as steroid hormones
and thyroid hormones, can diffuse through the cell membrane and interact with receptors in
the cytoplasm or nucleus.
The hormone receptors complex than alters gene transcription, causing the synthesis of
effector proteins mRNA. The hormone complex interacts with DNA in pairs; these may be
identical (homodimeric) or non-identical (heterodimeric) pairs

FUNCTION OF RECEPTORS
To propagate regulatory signals from outside to inside the effector cell when the
molecular speciescarrying the signal can‘t itself penetrate the cell membrane
To amplify the signals
To integrate various extracellular and intracellular regulatory signals.
To adapt to short term and long term changes in the regulatory melieu and maintain
homeostasis.

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DOSE RESPONSE RELATIONSHIP

DOSE – Amount of drug administered in the patient. e.g If 500 mg of paracetamol is taken dose
is 500mg.
RESPONSE - Effect shown by the body to a particular drug e.g Paracetamol is antipyretic drug
so response is it should bring body temperature to normal.
Drug +Receptor Drug-Receptor Complex Response

Dose Response Relationship

A relationship used to analyze a kind of response obtained after administering specific dose of
drug e.g If 10mg of ILLAPRAZOLE is administered response is it should inhibit formation of
proton pumps at 10mg specifically
Dose response relationship has two components
Dose plasma concentration relationship
Plasma concentration response relationship
Dose Response Curve
Relationship of dose to response can be illustrated by a graph which is called as dose response
curve. Dose response curve is required:-
Deciding dose of drug
Comparing dosage to percentage of people showing different effects
Intensity of response increases with increase in dose and dose response curve is rectangular
hyperbola
Dose response and log dose-response curves
Dose response curve is rectangular hyperbola
This is because drug-receptor interaction obeys law of mass action, accordingly
E = Emax × [D] /Kd × [D]
Where E = Observed effect of dose of drug
Emax = maximal response
Kd = dissociation constant of drug receptor complex

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Advantages of Plotting Log Dose Response Curves

 Wide range of drug doses can be displayed on graph.
 Comparison between agonist and antagonist becomes easy.
THRESHOLD
A dose below which there are no adverse effects from exposure to chemicals

TYPES OF DOSE RESPONSE CURVES

1. GRADED DOSE RESPONSE CURVES
Graded dose response curves are constructed for response that are measured on continuous
scale e.g heart rate
Graded dose response curves relates the intensity of response to size of dose hence used in
characterizing actions of drug Graded dose response means slight increase of drug brings
small increase in response. e.g increased dose of Histamine causes gradual contraction of
guinea pig ileum
Very low dose of histamine has no effect and response is obtained only beyond the threshold
dose of 20 mg
Very high dose of more than 50 mg has no additional effect and response remains constant at
this maximal levels
Graded dose response means the pharmacological effect of drug expressed in quality or
number such as heart rate by beat and blood pressure by mmHg

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2. QUANTAL DOSE RESPONSE CURVES

Quantal dose response curves are constructed for those drugs that elicit all or none response.
e.g presence or absence of epileptic seizures.
Indicates that given dose of drug has or has not evoked a certain effect in various subject
under investigation that is pharmacological effects are expressed in passive or negative.
Quantal dose response curves.
An experiment performed on 100 subjects and the effective dose to produce a quantal
response was determined for each individual.

DOSE RESPONSE CURVE INFORMATION

Drug potency and efficacy
Drug Potency refers to amount of drug needed to produce a response. Relative potency is more
meaningful than absolute potency. e.g If 10 mg of morphine=100 mg of pethidine, morphine is 10
times more potent than pethidine.
Drug Efficacy refers to ability of drug to elicit a response when it binds to a receptor
e.g Morphine produces a degree of analgesia not obtainable with any dose of aspirin hence
Morphine is more efficacious than aspirin

Drug potency and efficacy curves

Drug potency and efficacy curves
 Drug B is less potent but equally efficacious as drug A
 Drug C is less potent and less efficacious than drug A ,But equally potent and less efficacious
than drug B
 Drug D is more potent than drug A, B,& C but less efficacious than drugs A&B and equally
efficacious as drug C.

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SLOPE AND VARIABLITY

Effect of incremental increase in dose
Variability is reproductively of data different for different people

THERAPEUTIC INDEX
It is the ratio of LD50 to ED50. The ratio of LD1 and ED99 will give batter index safety of the
drug. The therapeutic index is a means of comparing the amount of a drug required to attain the
therapeutic level in 50% of patients to the amount that is lethal 50% of patients. It is expressed as
the ratio LD50/ED50.
A high therapeutic index is preferable, as the margin of safety between the dose that would be
sufficient to achieve therapeutic levels and that which would produce toxic effects is high.
Therapeutic Index = Median lethal dose/ Median effective dose
Or LD50/ED50

Quantal DRC showing LD50 and ED50.

ED50-Dose which will be therapeutically effective in 50% of animal
LD50- Dose which will on average kills 50% of animals in population.
MED- Minimum effective dose (the least dose that is likely to be effective). Also called toxic
dose low (TDL).
MTD- Maximum tolerated dose (minimum toxic dose) (more than this will produces signs of
toxicity). Also called highest nontoxic dose (HNTD).

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COMBINE EFFECT OF DRUG

Synergism: When the action of one drug is facilitated or increased by the other, they are said to
be synergistic. They are further of two types:
Additive: The effects of the two drugs are in the same direction and simply add up:
Effect of Drugs A + B = Effect of Drug A + Effect of Drug B
For example: combination of paracetamol and aspirin will provide the effect of both i.e.
antipyretic + analgesic.
Supra-additive: The effect of combination is greater than the individual effects of the
components:
Effect OF Drug A + B > Effect of Drug A +Effect of Drug B
For example: combination of levodopa and carbidopa increase the effect of drug, because
carbidopa inhibit the peripheral metabolism of levodopa.
Antagonism: When one drug decreases or abolishes the action of another, they are said to be
antagonistic.
Effect of Drugs A + B < Effect of Drug A + Effect of Drug B
For example: Glucagon and insulin on blood sugar level. Glucagon increase the blood sugar level
where insulin reduce the blood sugar level. Hence, if they are given in combination they will act
opposite to each other and the net effect will be nil.

FACTORS AFFECTING DRUG ACTION

Variation in response to the same dose of a drug between different patients and even in the same
patient on different occasions is a rule rather than exception.
Body size: It influences the concentration of the drug attained at the site of action. The average
adult dose refers to individuals of medium built. For exceptionally obese or lean individuals and
for children dose may be calculated on body weight (BW) basis:
Individual dose = BW (kg)/70 × average adult dose
It has been argued that body surface area (BSA) provides a more accurate basis for dose
calculation, because total body water, extracellular fluid volume and metabolic activity are better
paralleled by BSA.
Individual dose = BSA (m2)/1.7× average adult dose
The BSA of an individual can be calculated from Dubois formula:
BSA (m2) = BW (kg) 0.425 × Height (cm)0.725 × 0.007184
Age The dose of a drug for children is often calculated from the adult dose
Child dose= age/ (age+12) (young‘s formula)

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Child dose= Age/ 20 X Adult dose (Dilling‘s formula)

It can also be calculated (more accurately) on BW or BSA basis (see above), and for many drugs,
manufacturers give dosage recommendations on mg/kg basis. Average figures for children are
given below. However, infants and children are not small adults. They have important
physiological differences from adults. The newborn has low g.f.r. and tubular transport is
immature.
Similarly, hepatic drug metabolizing system is inadequate in newborns — chloramphenicol can
produce gray baby syndrome. Chloramphenicol can produce gray baby syndrome. Blood-brain
barrier is more permeable—drugs attain higher concentration in the CNS (accumulation of
unconjugated bilirubin causes kernicterus). Drug absorption may also be altered in infants
because of lower gastric acidity and slower intestinal transit.

Age Ideal BW (Kg) BSA (m2) % of Adult dose

Newborn 3.2 0.23 12.5

1 month 4.0 0.26 15
3 months 5.5 0.32 18
6 months 7.5 0.4 22
1 year 10 0.47 25
3 years 14 0.62 33
5 years 18 0.73 40
7 years 23 0.88 50
12 years 37 1.25 75

After the first year of life, drug metabolism is often faster than in adults. theophylline, phenytoin,
carbamazepine t½ is shorter in children. Also, higher per kg dose is needed for drugs which are
primarily excreted unchanged by kidney, e.g. daily dose of digoxin is about 8–12 μg/kg compared
to adult dose of 3–5 μg/kg. In the elderly, renal function progressively declines compared to
young adults. Drug doses have to be reduced. There is also a reduction in the hepatic microsomal
drug metabolizing activity and liver blood flow: oral bioavailability of drugs with high hepatic
extraction is generally increased, but the overall effects on drug metabolism are not uniform.
Sex: Females have smaller body size and require doses that are on the lower side of the range.
Subjective effects of drugs may differ in females because of their mental makeup. Maintenance

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treatment of heart failure with digoxin is reported to be associated with higher mortality among
women than among men. A number of anti-hypertensive have potential to interfere with sexual
function in males but not in females.
Species and race: Among human beings some racial differences have been observed, e.g. blacks
require higher and mongols require lower concentrations of atropine and ephedrine to dilate their
pupil. Β-blockers are less effective as antihypertensive in Afro-Caribbeans. Indians tolerate
thiacetazone better than whites. Considering the widespread use of chloramphenicol in India and
Hong Kong, relatively few cases of aplastic anaemia have been reported compared to its
incidence in the west. Similarly, quiniodochlor related cases of sub-acute myelooptic neuropathy
(SMON) occurred in epidemic proportion in Japan, but there is no confirmed report of its
occurrence in India despite extensive use.
Route of administration: Route of administration governs the speed and intensity of drug
response. Parenteral administration is often resorted to for more rapid, more pronounced and more
predictable drug action. A drug may have entirely different uses through different routes, e.g.
magnesium sulfate given orally causes purgation, applied on sprained joints—decreases swelling,
while intravenously it produces CNS depression and hypotension.
Environmental factors and several: Environmental factors affect drug responses. Exposure to
insecticides, carcinogens, tobacco smoke and consumption of charcoal broiled meat are well
known to induce drug metabolism. Type of diet and temporal relation between drug ingestion and
meals can alter drug absorption. Time of administration Subjective effects of a drug may be
markedly influenced by the setup in which it is taken. Hypnotics taken at night and in quiet,
familiar surroundings may work more easily. It has been shown that corticosteroids taken as a
single morning dose cause less pituitary-adrenal suppression.
Psychological factor: Efficacy of a drug can be affected by patient‘s beliefs, attitudes and
expectations. This is particularly applicable to centrally acting drugs, e.g. a nervous and anxious
patient requires more general anesthetic; alcohol generally impairs performance but if punishment
(which induces anxiety) is introduced, it may actually improve performance by relieving anxiety.
Disease: Not only drugs modify disease processes, several diseases can influence drug disposition
and drug action. Certain g.i. diseases can alter absorption of orally administered drugs. Similarly
liver disease can alter the metabolism of the drug and Kidney disease can alter the excretion of the
drug.
Other drugs: Drugs can modify the response to each other by pharmacokinetic or
pharmacodynamics interaction between them.

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ADVERSE DRUG REACTIONS

Adverse Drug Reaction: Any noxious change which is suspected to be due to a drug, occurs at
doses normally used in man, requires treatment or decrease in dose or indicates In future use of
same drug
Adverse Events: Any unwanted medical occurrence that may present during treatment a
pharmaceutical product but which does not necessarily have causal relationship with this
treatment.

Adverse
No need to have a Casual
Drug Events
relationship

Adverse
Causal relationship is
Drug
suspected / established
Reactions

Classification of ADRs
ADRs is very important as safe use of the medicinal product is critical issue for pharmaceutical,
industry, doctors, pharmacist and public. ADR may occur immediately or after prolonged use
after termination.
1. Type A (Augmented) Reactions
2. Type B (Bizarre) Reactions
3. Type C(Continuing) Reactions
4. Type D( Delayed) Reactions
5. Type E(End of use) Reactions
6. Type F( Failure of Therapy) Reactions

1. Type A (Augmented) Reactions

Dose related
Extension of Pharmacological effect.
Also called predictable or anticipated events.
Most frequent or less serious
Eg. Respiratory depression with opioids

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2. Type B (Bizarre) Reactions

Non dose related
Also called pharmacologically unexpected, unpredictable of Idiosyncratic reaction
Generally more serious and less frequent
Eg. Skin rashes with antibiotics

3. Type C(Continuing) Reactions

Dose & time related
Associated with long term use
Eg. NSAID induced renal failure

4. Type D( Delayed) Reactions

Apparent only sometime after use of drug
Timing of these may make them more difficult to detect.
e.g. Thalidomide in first trimester caused phocoelia limb defects.

5. Type E (End of use) Reactions

Associated with the withdrawal of a medicine
e.g. Insomnia, anxiety & perceptual disturbances following withdrawal of benzodiazepines.

6. Type F( Failure of Therapy) Reaction

Failure of therapy which can be due to diverse causes such as inadequate information on the
consumption, quality of drug etc.
e.g. Anti-tubercular therapy

Prevention of ADR
By taking following steps, chances of ADR can be minimized/ prevented:-
Avoid inappropriate drugs in the context of clinical conditions
Use right dose, route, frequency based on patient variables
Elicit medication history and history of allergy
Rout of drug interactions
Adopt right technique of medication and follow adequate monitoring

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Dimensions of AE

Dimensions of adverse event

Intensity Seriousness Expectedness Relatedness

Mild
Non Serious Expected Related
Moderate
Serious Unexpected Unrelated
Severe

The tern severe is often used to describe the intensity (severity) of a specific event (as in mild,
moderate, or severe myocardial infraction). The event itself, may be of relatively minor medical
significance (such as severe headache) While the term serious is based on patient‘s event
outcome or action criteria.

Several terms commonly used to describe the adverse effect of drug therapy:-
Side effects
Side effect as name indicates it is the side wise effect along with main effect of drug which was
taken intentionally. Side effects are often associated with the therapeutic effect and it is well
known in advance prior to drug administration.
Drug toxic effects
Toxic effect is the result of excessive pharmacological action of drug due to over dosage or
prolonged use. Over usage may be intentional or relative related with therapeutic dose. The
effects are predictable and dose related.
Drug Abuse
Drug abuse is a somehow misuse of drug. In this case people use the drug not for the intended or
prescribed purpose but for other narcotic purpose. There are several examples- codeine was a
good antitussive drug but few people used that for narcotic purpose.
Intolerance
It is the appearance of characteristic toxic effects of a drug in an individual at a therapeutic dose.

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It is a converse of tolerance and indicates a low threshold of individual to the action of drug.
Idiosyncrasy
It is genetically determined abnormal reactivity to a chemical. The drugs interact with some
unique feature of the individual, not found in majority of subjects, and produce the
uncharacteristic.
Drug Allergy
It is an immunologically mediated reaction producing stereo type symptoms which are unrelated
to the Pharmacodynamics profile of the drug, generally occur even with much smaller dose and
have different time course of onset and duration. This is also called drug hypersensitivity.
Drug dependence
Drug capable of altering mood and feeling are liable to repetitive use to derive euphoria,
withdrawal from reality, social adjustment etc. drug dependence is a state in which use of drug for
personal satisfaction is accorded a high priority than other basic needs. It is of several types-
psychological dependence, physiological dependence.
Photosensitivity
It is a cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation.
This may of two types- phototoxic and photo allergic.
Drug withdrawal
Physical and mental symptoms that occur after stopping or reducing intake of a drug. The
characteristics of withdrawal depend on what drug is being discontinued.
Teratogenicity
It refers to the capacity of drug to cause fetal abnormalities when administered to the pregnant
woman. This may cause disturbance in the organogenesis.
Carcinogenicity
The term carcinogen denotes a chemical substance or a mixture of chemical substances which
induce cancer of increase incidence.
Mutagenicity
It refers to the capacity of drug to cause genetic defects and cancer respectively. Usually oxidation
of the drug results in the production of reactive intermediate which affects gene and may cause
structural changes, in the chromosome.
Drug induces disease
It is defined as the unintended effect of a drug that results in mortality or morbidity with
symptoms sufficient to prompt a patient to seek medical attention and to require hospitalization
and may persist even after the offending drug has been withdrawn.

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DRUG INTERACTIONS (PHARMACOKINETIC AND PHARMACODYNAMICS

DEFINITION
Drug interaction is defined as the pharmacological activity of one drug is altered by the
concomitant use of another drug or by the presence of some other substance.
The Drug whose Activity is effected by such an Interaction is called as a “Object drug.” The
agent which precipitates such an interaction is referred to as the “Precipitant”.
Types of drug Interactions
1. Drug-drug interactions.
2. Drug-food interactions.
3. Chemical-drug interactions.
4. Drug-laboratory test interactions.
5. Drug-disease interactions.

The Net effect of a Drug Interaction is:

Generally quantitative i.e. increased or decreased effect.
Seldom qualitative i.e. Rapid or slower effect.
Precipitation of newer or increased adverse effect.

Drug interactions are:

Mostly undesirable
Rarely desirable (beneficial): for eg.,enhancement of activity of penicillin‘s when
administered with probenecid.

Factors contributing to drug interactions:

1. Multiple drug therapy.
2. Multiple prescribers.
3. Multiple pharmacological effects of drug.
4. Multiple diseases/predisposing illness.
5. Poor patient compliance.
6. Advancing age of patient.
7. Drug-related factors.

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Mechanisms of drug interactions: The three mechanisms by which an interaction can develop
are-
1. Pharmaceutical interactions.
2. Pharmacokinetic interactions.
3. Pharmacodynamic interactions.
Pharmaceutical interactions:
Also called as incompatibility. It is a physicochemical interaction that occurs when drugs are
mixed in i.v . Infusions causing precipitation or inactivation of active principles. Example:-
Ampicillin ,chlorpromazine & barbiturates interact with dextran in solutions and are broken down
or from chemical compounds.
Pharmacokinetic Interactions:
“These interactions are those in which ADME properties of the object drug are altered by the
precipitant and hence such interactions are also called as ADME interactions”. The resultant
effect is altered plasma concentration of the object drug. These are classified as:
1. Absorption interactions
2. Distribution interactions
3. Metabolism interactions
4. Excretion interactions.
Absorption interactions
Are those where the absorption of the object drug is altered. The net effect of such an interaction
is:
 Faster or slower drug absorption.
 More, or, less complete drug absorption.
Major mechanisms of absorption interactions are:
1. Complexation and adsorption.
2. Alteration in GI pH.
3. Alteration in gut motility.
4. Inhibition of GI enzymes.
5. Alteration of GI micro flora.
6. Malabsorption syndrome.

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ABSORPTION INTERACTIONS
Object drug Participant Influence on object drug
Complexation & adsorption
Ciprofloxacin, pencillamine Antacids, food & minerals Formation of poorly soluble
supplements containing al, and absorbable complex
mg, fe, zn & ca2+ ions with such heavy metal ions.
Alteration of GI pH
Sulphonamides, Antacids Enhanced dissolution and
Aspirin, ferrous sulphate absorption rate.
Sodium bicarbonate, Decreased dissolution and
Calcium carbonate enhance absorption
Alteration of gut motility
Aspirin, Diazepam, Metoclopramide Rapid gastric emptying,
levodopa, mexiletine increased rate of absorption.
levodopa, Mexiletine anti-cholinergic delayed decreased rate of absorption
lithium carbonate, gastric emptying
Alteration of GI micro flora
Digoxin anti-biotic Increased bioavailability due
to destruction of bacterial
flora that inactivates digoxin
in lower intestine.
Malabsorption syndrome
vitamin a,b12, digoxin Neomycin Inhibition of absorption due
to mal.

DISTRIBUTION INTERACTIONS: Are those where the distribution pattern of the object drug
is altered: The major mechanism for distribution interaction is alteration in protein-drug binding.
Competitive displacement interactions
Object drug Participant0 Influence on object drug
Displaced drug Displacer
Anti-coagulants Phenylbutazone, Increased clotting time.
Chloral hydrate Increased risk of hemorrhage.
Tolbutamide Sulphonamides Increased hypoglycemic effect

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METABOLISM INTERACTIONS: Are those where the metabolism of the object drug is
altered. Mechanisms of metabolism interactions include:
1. Enzyme induction: Increased rate of metabolism.
2. Enzyme inhibition: Decreased rate of metabolism. It is the most significant interaction in
comparison to other interactions and can be fatal.
Metabolism interactions
Object drug Precipitant Influence on object drug
Enzyme Induction
Corticosteroids, Barbiturates Decreased plasma levels; decreased
Oral contraceptives, efficacy of object drugs
Coumarins, phenytoin
Oral contraceptives, rifampicin decreased plasma levels
Oral hypoglycemic
Enzyme Inhibition
Tyramine rich food MAO inhibitors Enhanced absorption of unmetabolized
tyramine
Coumarins metronidazole increased anti-coagulant activity
phenyl butanone

EXCRETION INTERACTIONS: Are these where the excretion pattern of the object drug is
altered.
Excretion Interactions
Object drug Precipitant I Influence on object drug
Changes in active tubular secretion
Penicillin, cephalosporin, probenicid Elevated plasma levels of acidic
and nalidixic acid drugs
Changes in urine pH
Amphetamine Antacids, Thiazides, Increased passive reabsorption of
Acetazolamide basic drugs. Increased risk of
toxicity
Changes in renal blood flow
Lithium Bicarbonate NSAIDS Decreased renal clearance of
lithium. Risk of toxicity

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Major mechanisms of excretion interactions are-

 Alteration in renal blood flow
 Alteration of urine PH
 Competition for active secretions
 Forced diuresis

PHARMACODYNAMIC INTERACTIONS:
Are those in which the activity of the object drug at its site of action is altered by the precipitant.
Such interactions may be direct or indirect. These are of two types
1. Direct pharmacodynamics interactions.
2. Indirect pharmacodynamics interactions.
Direct pharmacodynamics interactions:
In which drugs having similar or opposing pharmacological effects are used concurrently. The
three consequences of direct interactions are
1. Antagonism.
2. Addition or summation.
3. Synergism or potentiation.
Antagonism: The interacting drugs have opposing actions Example: Acetylcholine and
noradrenaline have opposing effects on heart rate.
Addition or summation: The interacting drugs have similar actions and the resultant effect is the
some of individual drug responses Example: CNS depressants like sedatives and hypnotics etc
Synergism or potentiation: It is an enhancement of action of one drug by another Example:
Alcohol enhances the analgesics activity of aspirin.

Indirect pharmacodynamics interaction:

In which both the object and the precipitant drugs have unrelated effects. But the latter in some
way alerts the effects but latter in some way alerts the effects of the former.
Example: salicylates decrease the ability of the platelets to aggregate thus impairing the
Homeostasis if warfarin induced bleeding occurs.
Reducing the risk of drug interactions:
 Identify the patient‘s risk factors.
 Take through drug history.
 Be knowledge about the actions of the drugs being used.
 Consider therapeutic alternatives.

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 Avoid complex therapeutic regiments when possible.

 Educate the patient.
 Monitor therapy.

Consequences of drug interactions:

The consequences of drug interactions may be:
Major: Life threatening.
Moderate: Deterioration of patients‘ status.
Minor: Little effect.

Influence of smoking on drug interactions:

Smoking increases the activity of drug metabolizing enzymes in the liver, with the result that
certain therapeutic agents. Example: Diazepam, propoxyphene, theophylline, olanzapine. Are
metabolized more rapidly, and their effect is decreased

Influence of alcohol on drug interaction:

Chronic use of alcohol beverages may increases the rate of metabolism of drugs such as warfarin
and phenytoin, probably by increasing the activity of hepatic enzymes.
 Acute use of alcohol by non-alcoholic individuals may cause an inhibition of hepatic
enzymes.
 Use of alcoholic beverages with sedatives and other depressants drugs could result in an
excessive depressant response.

Influence of Food on Drug Interaction:

Food affects the rate and extent of absorption of drugs from the GI tract. Example: Many anti
biotic should be given at least 1hr before or 2hr after meals to achieve Optimal absorption.
 The type of food may be important with regard to the absorption of concurrently
administered Drugs. Example: Dietary items such as milk and other dairy products that
contain calcium may decrease. The absorption of tetracycline and flour quinolone
derivatives.
 Diet also may influence urinary pH values.

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DRUG DISCOVERY AND CLINICAL EVALUATION OF NEW DRUGS

Drug Development Process
Drug development is basically bringing out a new product into the market. On average it takes
about 10-15 years to develop a drug from its discovery to getting approved for marketing it
available in the market for its usage.
Drug Development process can be divided into:
Discovery Phase
Pre-Clinical Phase
Clinical Phase
Market Phase

Drug Discovery
In the past most drugs have been discovered either by identifying the active ingredient from
traditional remedies or by serendipitous discovery.
But now we know diseases are controlled at molecular and physiological level.
Also shape of a molecule at atomic level is well understood.
―A process that starts with the identification of disease and therapeutic target of interest and
include methodology, assay development ,lead identification and characterization in vitro
,formulation and animal pharmacological studies ,pharmacokinetics and safety studies in animals
and clinical studies in the human .‖

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Drug Discovery

DRUG DISCOVERY PHASES

Discovery phase is the first phase of drug development process which includes the following:

Target Selection Lead Discovery

Drug Target Target Lead Lead

Discovery Identification Validation Identification Optimization

To identify To improve that Finding a Finding a

molecular manipulating compound compound
targets which the molecular that bind to that bind
are involved target can target better to the
in disease provide target
progression therapeutic
benefit to
patients.

Discovery phase overview

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TARGET SELECTION
Target selection in drug discovery is defined as the decision to focus on finding an agent with a
particular biological action that is anticipated to have therapeutic utility
Target identification: to identify molecular targets that is involved in disease progression.
Target validation: to prove that manipulating the molecular target can provide therapeutic
benefit for patients.

Cellular level

Target
validation can Whole animal
be done on model level

Molecular
Level

Target Validation
LEAD DISCOVERY
Lead compound is a chemical that has pharmacological/biological activity likely to be
therapeutically useful, but may still have sub-optimal structure that structure that requires
modification to fit better to the target.
Lead Identification: Find a compound that bind to target.
Lead optimization: Find compound that bind better to the target.

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PRE-CLINICAL PHASE
In this phase, research in animal model, ex vivo and in vivo experiments takes place to check the
safety and efficacy of new potential compound which is carried out according to regulatory
guidelines. Major areas are:
Pharmacodynamics studies in vivo in animals, In vitro preparation
Absorption, distribution , elimination studies (pharmacokinetics)
Acute, sub-acute, chronic toxicity studies (toxicity profile)
Therapeutic index (safety & efficacy evaluation)

Animal Studies comprises of:-

Toxicology Studies: The efects of larg doses, carcinognicity,

mutagenicity, teratogenicity

Pharmacodynamics Studies: The machanism of action and

estimates of therapeutic effects.

Pharmacokinetic studies: Looking how substance is absorbed,

distributed, metabolized and eliminationinthe animal

OBJECTIVES OF PRECLINICAL STUDIES

The purpose of pre-clinical study is to develop adequate data to decide that it is reasonably
safe to proceed with human trials of the drug.
Means, a laboratory test of a new drug or a new medical device, usually done on animal
subjects, to see if the treatment really works and if it is safe to test on humans
However the main objective is to collect the data to submit to the FDA for IND filing.

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IND APPLICATION FILING

Once preclinical studies have indicated the safety and efficacy of a drug an IND application has to
be filed with the regulatory authorities. For obtaining regulatory Approval for Phase I, phase II
and Phase III clinical evaluation. Contents of IND application:
Preclinical Data (All data from animal studies)
Information on composition and source of drug
Chemical and manufacturing information
Proposed clinical plans and protocol
Ethical Committee Clearance

CLINICAL PHASE
The clinical studies test the potential treatments (drug, device or biologics like vaccines human
volunteers or patients to see whether they should be further investigated or approved for the wider
use in general population.
Types of clinical trial
 Randomized
 Blinded or open label
 Prospective or retrospective
 Placebo
 Pilot study.
 Cross-over study.

Randomized: Subjects have equal chance to be assigned to one of two or more groups just like
tossing of coin. – One group gets the most widely accepted treatment (standard treatment) – The
other gets the new treatment being tested – All groups are as alike as possible; removes the
probability of bias.
Open label trial Doctor and patient know which drug is given
Blinded clinical trial
Single Blind: the patient doesn‘t know which treatment he/she is getting
Double Blind: neither doctor nor patient knows
Prospective: Patients are enrolled for the study before any treatment begins Progress of patients
is monitored during course of treatment
Retrospective: Past case records & other statistical data are used for analysis Investigator has to
rely on methods employed & data available

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Placebo Study:
It is an inert medicament given in the garb of medicine.
It resembles the active drug in physical properties but does not have any pharmacological activity.
The new treatment is tested against a placebo.
Pilot Study:
A small study that helps to develop a bigger study.
Advantage
 To find out possible difficulties
 To help with design of the bigger, more pivotal study.
Cross-Over Study: Two types of treatment are studied in the same group. • Before giving 1st
treatment baseline observations are made for certain period – ―Run-in period‖. • When one
treatment is over, before starting 2nd treatment some time is allowed for the effect of treatment to
completely wash out – ―Wash-out period‖.

PHASE OF CLINICAL TRIALS

PHASE 0 STUDY /MICRODOSING

Study of new drug in micro doses to derive PK information in human before undertaking
phase I studies is called PHASE O
Micro dose: Less than 1/100 of the dose of a test substance calculated to produce
pharmacological effect with a max dose ≤100 micrograms
Objective:
 To obtain preliminary Pharmacokinetic data.
 Preclinical Data: Sub acute toxicity study in one species by two routes of administration.

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Advantages:
Less chances of adverse effects
Short duration
Less no. of volunteers
Reduced cost of development
Reduced drug development time
Limitations:
 Study mainly based on PK parameters - not efficacy and safety based
 Agents having different kinetic characteristics between micro dose and full dose are not
evaluated by phase 0 trials
 The laboratory parameters are very limited and expensive, researchers have to depend on
BA/BE labs

PHASE I CLINICAL TRIAL

First stage of testing in human subjects.
Designed to assess the safety, tolerability, PK and PD of drug.
20-80 healthy volunteers; Duration: 6-12 months.
Patients: Anticancer drugs, AIDS therapy.
The aim of a Phase I trial is to determine the maximum tolerated dose (MTD) of the new
treatment.
Kinds of Phase I:
SAD: Single ascending dose studies.
MAD: Multiple ascending dose studies.
Food Effect: Investigates differences in absorption caused by food.
SUBJECTS: • Healthy human volunteers: Commonly used.
Patient Volunteers: Cytotoxic drugs, AIDS therapy -Patients in advanced stage of disease.
LIMITATIONS:
Trial restricted to homogenous subjects.
Performance extrapolated to heterogeneous market place.

PHASE II CLINICAL TRIAL

It is a Therapeutic Exploratory Trial consists of 100-500 Subjects.
To confirm effectiveness, monitor side effects, & further evaluate safety.
First in patients (who have the disease that the drug is expected to treat).

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Duration: 6 months to several years.

Optimum dose finding:
Dose efficacy relationship
Therapeutic dose regimen
Duration of therapy
Frequency of administration
Therapeutic window
For New Actions of a marketed drug, start with Phase II (Phase I exemption obtained).
Phase II Study Types:
Phase IIA: Designed to assess dosing requirements.
Phases IIB: Designed to study efficacy.

PHASE III CLINICAL TRIALS

It is a Therapeutic confirmatory trial.
Target population: several 1000 to 3000 patients.
Duration: Takes a long time, up to 5 years.
To establish efficacy of the drug against existing therapy in larger number of patients, method
of usage, & to collect safety data etc.
To assess overall and relative therapeutic value of the new drug Efficacy, Safety and Special
Properties

Subtypes:
Phase IIIA: To get sufficient and significant data.
Phase IIIB: Allows patients to continue the treatment, Label expansion, additional safety data.
Phase III B studies are known as "label expansion‖ to show the drug works for additional types of
patients/diseases beyond the original use for which the drug was approved for marketing.

End of Clinical Trial Activities

Sponsor: Expert Committee review of Efficacy, safety and potential sales (Profit).
Go-No Go decision to file new drug application with DCGI.
Expert review by DCGI‘s Committee
DCGI approval.
NCE marketed Phase IV begins 2021.

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NDA: New Drug Application

NDA Refers to New Drug Application. Formal proposal for the FDA/DCGI to approve a new
drug for sale. Sufficient evidences provided to FDA/DCGI to establish:
Drug is safe and effective.
Benefits outweigh the risks.
Proposed labeling is appropriate.
NDA contains all of the information gathered during preclinical to phase III.

PHASE IV CLINICAL TRIALS

Post Marketing Surveillance (PMS). No fixed duration / patient population. Helps to detect rare
ADRs, Drug interactions and also to explore new uses for drugs [Sometimes called Phase V].
Periodic Safety Update Reports : To be submitted by the manufacturer every 6 months for 2 yrs
and then annually for next 2 yrs after marketing approval.
Harmful effects discovered may result in a drug being no longer sold, or restricted to certain uses

Objectives of phase IV:

Confirm the efficacy and safety profile in large populations during practice.
Detect the unknown/rare adverse drug reaction/s.
Evaluation of over-dosage.
Identifications of new indications.
Dose refinement: Evaluation of new formulations, dosages, durations of treatment.

Reporting of ADR:
The ADR can be reported to a formal reporting system such as: WHO International System
USFDA- Medwatch UK- Yellow card system INDIA- National Pharmacovigilance Programme
(CDSCO)

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PHARMACOVIGILANCE
Pharmaco (Greek) = drug or medicine Vigilare (Latin) = To watch, keep awake or
alert
Pharmacovigilance is the science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other possible drug-related problems. (As
per WHO guidelines)
Overall Process
Discover
Develop
Proof of Safety
Proof of Evidence
Submit

Clinical trial
A systematic study on pharmaceutical products in human subjects (including patients and other
volunteers) in order to discover or verify the effects of, and/or identify any adverse reaction to
investigational products, and/or to study the absorption, distribution, metabolism and excretion of
the products with the objective of ascertaining their efficacy and safety.
Clinical Trials: Snap shot

Adverse Event
Any untoward medical occurrence that may present during treatment with a pharmaceutical
product at any dose, but which does not necessarily have a causal relationship with this treatment.

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Adverse drug reaction

A response which is noxious and unintended, and which occurs at doses normally used in humans
for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological
function. (WHO).

Serious Adverse Event

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any
dose:
 results in death,
 is life-threatening,
 requires inpatient hospitalization or prolongation of existing hospitalization,
 results in persistent or significant disability/incapacity, or
 is a congenital anomaly/birth defect?
 is any other important medical event?

History of Pharmacolvigilance
1848: The Lancet starts collecting notifications of side effects after a death caused by anesthesia.
1906: US Federal Food and Drug Act require that pharmaceuticals be ―pure‖ and ―free of any
contamination‖.
1937: USA: 107 lethal cases after diethylenglycol was mistakenly used to solubilize
sulphanilamides.
1848: The Lancet starts collecting notifications of side effects after a death caused by anesthesia.
1906: US Federal Food and Drug Act require that pharmaceuticals be ―pure‖ and ―free of any
contamination‖.
1937: USA: 107 lethal cases after diethylenglycol were mistakenly used to solubilize
sulphanilamides.
1967: Start of WHO Programme for International Drug Monitoring.
1976: Drugging of the Americas: inadequacy of safety information.
1990: ICH - elaboration of intra-regional requirements for safety starts

The thalidomide tragedy

20th Century
1962 – A new sleeping pill is found to have caused birth defects in thousands of babies born in
Western Europe. Terratogenic effects in new borns.

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Dr. Frances Kelsey, FDA kept Thalidomide off the U.S. Market

Sulfanilamide tragedy
Sulfanilamide had been used safely for some time in tablet and powder form to treat streptococcal
infections
S.E. Massengill Co., a pharmaceutical company dissolved the drug in diethylene glycol and sold
it in the liquid form after testing for flavor and colour
Toxicity testing was not done and resulted in deaths of 100 children in 1937
The company was sued for misbranding
The current status WHO International drug monitoring programme was laid in 1971.
2000:
WHO UMC provided guidelines for setting up a pharmacovigilance center.
CIOMS and ICH were established for development of pharmacovigilance world wide.
The UK ‗yellow card‘ system for the reporting of suspects adverse effects came into being
in1964
1968 WHO drug monitoring programme was laid
Classical example of serious and unexpected adverse reactions

Medicine Adverse reaction

Aminophenazone(amidopyrine) Agranulocytosis
Chloramphenicol Aplastic anaemia
Clioquinol Myelooptic neuropathy (SMON)
Erythromycin estolate Cholestatic hepatitis
Fluothane Hepatocellular hepatitis
Methyldopa Haemolytic anaemia
Oral contraceptives Thromboembolism
Practolol Sclerosing peritonitis
Reserpine Depression

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Pharmacovigilance
When a medicine is released into the market there is still uncertainty about the safety of the
product.
Once marketed, the drug is openly available for the use of large population, which brings a major
safety concern.
In order to prevent unnecessary sufferings by patients, it is essential to have a drug safety
monitoring system in place in every country.
Thalidomide disaster
Thalidomide was first marketed in the late 1950s as a sedative and was used in the treatment of
nausea in pregnant women.
Within a few years of the widespread use of thalidomide in Europe, Australia, and Japan,
approximately 10,000 children were born with phocomelia, leading to the ban of thalidomide in
most countries in 1961.
The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant
testing of pharmaceuticals prior to their introduction into the marketplace

Need of Pharmacolvigilance
Unreliability of preclinical data
Well controlled conditions
Small and specific sample size
Pressure from various groups to reduce time to approval
Changing pharmaceutical marketing strategies
Aggressive marketing
Direct to customer advertising
Launch in many countries at a time
Changing physician and patient preferences
Increasing use of newer drugs
Increasing use of drugs to improve quality of life
Shift of supervised to self-administered therapy
Easy accessibility
Increasing conversion of prescription drugs to OTC drugs
Easy access by internet
Easy availability of complimentary medicines
Easy availability of substandard drugs

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The scope of Pharmacolvigilance

To improve patient care and safety
To improve public health and safety
To contribute to the assessment of benefit, harm, effectiveness and risk of medicines
To promote education and clinical training
To promote effective communication to the public.
To promote rationale and safe use of medicines.

Goals of Pharmacolvigilance
Early detection of unknown safety problems
Detection of increase in frequency of ADR‘s
Identification of risk factors
Quantifying risks
Preventing patients from being affected unnecessarily

Aim of Pharmacolvigilance
Improve patient care and safety in relation to the use of medicines and all medical &
paramedical interventions.
Improve public health and safety in relation to the use of medicines.
Contribute to the assessment of benefit, harm, effectiveness and risk of medicines.
Encouraging their safe, rational and more effective (including cost-effective) use.
Promote understanding, education and clinical training in Pharmacolvigilance and its
effective communication to the public.

PHARMACOVIGILANCE- A SHARED RESPONSIBILITY

Company – legally and morally responsible for monitoring their product.
Regulatory authorities – are responsible for the safety of the drugs they license
Doctors – responsible to patients
Pharmacist & nurse – responsible to patients

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RA
Company PV Doctors

Pharmacist/HCP

Sources of Pharmacolvigilance
Pre-clinical studies
Clinical studies (pre- and post-marketing)
Spontaneous adverse reaction reporting
National
International
Epidemiological studies
Case-control (one effect/many risk factors)
Cohort (one risk factor/many possible effects)
Data collected for other purposes
Routine statistics
Databases of prescription and outcomes

Why is Pharmacolvigilance important

"Dying from a disease is sometimes unavoidable. But, dying from an adverse drug reaction is
unacceptable".
-Dr Vladimir Lepakhin
Why is Pharmacolvigilance important?
 Bottlenecks in clinical studies
 Monitoring by Health Authorities
 To Increase in awareness among the physicians and the patients about adverse event reporting
for better quality of life
 Early detection of unknown safety problems
 Detection of ADR‘s with increase in frequency.
 Identification of risk factors
 Quantification of risks
 Prevention of patients‘ unnecessary sufferings

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Minimum Safety Information

 An identifiable patient
 An identifiable reporter
 A suspect drug or biological product
 An adverse event

Sources of adverse event reports

Pre-clinical studies
Clinical studies (Pre-post marketing)
Spontaneous Reports Literature, Internet, Consumers/HCPs &Other Sources –Lay press/ Media
Epidemiological studies
1.Case control
2.Cohort studies
Data collected for other purposes
1.Routine statistics
2.Databases for prescription and outcomes

ORGANIZATIONS WHICH PLAY A KEY ROLE IN PHARMACOVIGILANCE

World Health Organization (WHO)
International Conference on Harmonization (ICH)
Council for International Organizations of Medical Sciences (CIOMS)
The International Society of Pharmacovigilance (ISoP)
Key regulatory agencies
United States Food and Drugs Administration (USFDA)
European Medicines Agency (EMA)
Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK)
Pharmaceuticals and Medical Devices Agency (PMDA) in Japan
Health Canada
Therapeutic Goods Administration (TGA) in Australia
Chinese Food and Drug Administration (CFDA)

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LONG ANSWER TYPE QUESTIONS (10 Marks)

1. Explain signal transduction mechanism and explain G-Protein coupled receptor
2. Define drug interaction. Explain pharmacokinetic and pharmacodynamics type of drug
interaction with suitable examples.
3. Explain drug discovery process and elaborate different phases of clinical trial.

SHORT ANSWER TYPE QUESTIONS (5 Marks)

1. Define receptors. Explain various types of receptors family in short
2. Write short notes on adverse drug reaction with suitable examples.
3. What are various factors modifying drug action.
4. Write short notes on dose response relationship
5. What do you understand by combined effect of drugs? Give your answer with example.
6. What is Trans- membrane enzyme linked receptor.
7. What do you understand by mechanism of drug action?
8. Explain pharmacokinetic and pharmacodynamics in short along with their related examples.
9. Explain Pharmacolvigilance. Why it is important?
10. Explain combined effect of drugs with suitable examples
11. Explain essential drug concept

VERY SHORT ANSWER TYPE QUESTIONS (2 Marks)

1. Write a note on pharmacodynamics drug interaction.
2. Write a note on pharmacokinetic drug interaction.
3. Write a note on preclinical evaluation.
4. Write a note on drug interactions.
5. Define Pharmacolvigilance.
6. Enlist receptor theory.
7. Define phase of clinical trials.
8. Define therapeutic Index.
9. Write a note on drug discovery.
10. Write a note on ADR.
11. Enlist different type of receptor.

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