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INTRODUCTION TO

PHARMACOLOGY
Leeland Anthony L. dela Luna,
Pharm.D, R.Ph

PROCEED

VERIFY

REMEMBER

UNDERSTAND

THINK

READ

How to PROCEED with the lesson

PROFESSION

Science of drugs

PHARMACY
Science of:
Identification
Selection CHEMISTRY!
Preservation
Standardization
Compounding
Dispensing
OF MEDICINAL SUBSTANCES

How drugs

WORK!

PHARMACOLOGY
Science about:
Effects of drugs on
the body

BIOLOGY +
CHEMISTRY

WHO definition of a DRUG


NATURAL like
leaves of plants

Something that is
Produced
SYNTHETIC

Molecules in
RESEARCH are
still drugs

Any substance or product


Contraceptive
that is used or intended to be used
pills or Vaccines
to modify, explore physiological system
DIAGNOSTIC
or cure pathological states
SUBSTANCES like
Inulin or dyes are
for the benefit of the recipient
still drugs
Conventional
definition of a
drugCHEMICAL
THAT CURES!!!

Which means.
All CHEMICALS that are
Vaccines
Diagnostic agents
Cures diseases
Relieves symptoms
Prevents conception

ARE ALL DRUGS!!!

A few relevant DEFINITIONS

PHARMA COGNOSY
About DRUGS

To KNOW

The Science of IDENTIFICATION of Drugs


*(most used drug source are plants)*

CLINICAL PHARMACY
Related to interaction between
DOCTOR and PATIENT

Related to interaction between


PATIENT and PHARMACIST

Patient bridges the gap between


DOCTORS and PHARMACIST

Involves the cooperation of

PHARMACIST with PHYSICIANS


In educating patients about compliance, and
counselling him on how to take the medicines and
monitor errors in drug therapy

PHARMACO KINETICS
About DRUGS

About MOVEMENTS

Movement of Drugs in the body


Study of the ADME System

Absorption
Distribution
Metabolism
Excretion

What the BODY


does to the DRUG

PHARMACO DYNAMICS
About DRUGS

Dynamo = POWER

Power of the drug ACTION/efficacy of DRUGS


Study of the action, biologic & therapeutic
effects of drugs
Consequences of drug binding with its receptor

What the DRUG


does to the BODY

THERAPEUTICS
Deals with:
CURE of the disease (i.e. TB, Malaria)
RELIEF of the symptoms (i.e. Fever, Breathlessness)

It INVOLVES both:
PHARMACOLOGIC Tx (with drugs)
NON PHARMACOLOGIC Tx (i.e. exercise, life style
modification, diet modification, etc.)

TOXI COLOGY
About POISONS

The study of POISONS


Science of Poisons which
includes DETECTION of the
signs, MEASUREMENT of
poisons and prevention
and treatment of poisons

To STUDY
QUALITATIVE ASSESSMENT
Finding the NATURE of the
poison

QUANTITATIVE ASSESSMENT
Finding the AMOUNT of the
poison ingested

CHEMOTHERAPY
Effects of drugs on the cell division / on the
cells of:
NORMAL HOST CELL
MICROORGANISMS
MALIGNANT CELLS

PHARMACOEPIDEMIOLOGY
It is the study of effects and uses of drugs in
large number of people

PHARMACO-ECONOMICS
It is the analysis of the cost of drug therapy to
the healthcare system and the society.

PHARMACOGENOMICS
Science that examines the:
Variation in genes that dictates the drug response
of:
Humans
Microbes
Tumors

Explores the ways these variations can be used to


predict whether a response will be a:
Good response
Bad response
No response

DRUG NOMENCLATURE
CHEMICAL NAME
It says something about the chemical composition
Paraacetyl amino phenol

GENERIC NAME
Name assigned by a SCIENTIFIC BODY/AUTHORITY
Paracetamol

BRAND/TRADE NAME
Name assigned by the MANUFACTURER
Biogesic / Calpol

Pharmacology

Pharmacodynamic Principles
Levels of Drug
Action

Molecular
Cellular
Tissue
System

Molecular Targets
Hormones and
neurotransmitter
receptors
Enzymes
Carrier molecules
Ion channels
Idiosyncratic targets
Nucleic acids

Levels of Drug Action


Mechanism

Propranolol

Rifampin

Molecular

Competitive & reversible antagonist of


EPI & NE on -adenoceptor

Bind to and blocks the


activity of RNA
polymerase in the
mycobacterium

Cellular

Prevents -adrenergic agonism from


elevating intracellular cAMP, initiating
protein phosphorylation, Ca++
mobilization & oxidative metabolism

Inhibits mycobacterial
RNA synthesis and
thereby kills the
mycobacterium

Tissue

Prevents -adrenergic agonism from


increasing contractile force and rate of
the heart

Prevents damage to lung


tissue arising as a result
of mycobacterial
infection

System

Improves cardiovascular function

Prevents loss of lung


function caused by TB

HOW DRUGS ACT?


BY ACTING ON A SPECIFIC (MOLECULE)TARGET
SUCH AS:
1. RECEPTOR
2. ION-CHANNEL
3. ENZYME
4. CARRIER/TRANSPORTER

Receptor

RECEPTORS

AGONIST

EFFECTS!!!
Receptor

Ion channel opening/closing


Enzyme activation/inhibition
Ion channel modulation
DNA transduction

RECEPTORS

ANTAGONIST

AGONIST
Blocks the active site
of the receptor

Receptor
The agonist will be
deflected; will not
bind to the active site,
thus NO EFFECT

Ion Channels

Ions in the extracellular


environment

DRUG
Receptor

Ion Channels

Drug binding causes the


channel to open allowing
Ions to enter

Ions in the extracellular


environment

DRUG
Receptor

Ion Channels

Drug closes the ion channel.


MODULATES Ion channels

Ions in the extracellular


environment

DRUG
Receptor

Ion Channels

Permeation of the
channel is blocked.

Enzymes

DRUG

Enzymes

Drug inhibits the active


site of the enzyme

In the presence of an inhibitor, the enzyme


COULD NO LONGER METABOLIZE the object drug.

Enzymes

DRUG

Enzymes

Produce an ABNORMAL
metabolite

DRUG
Produce an ACTIVE metabolite

Enzymes

Types of Receptor-Effector
Linkage
(Signaling Mechanisms)

Types of Receptor-Effector Linkage


(Signaling Mechanisms)
Channel-linked
(ionotropic)

milliseconds
Nicotinic
ACh receptor

G-protein coupled receptors


(metabotropic)

seconds
Muscarinic
ACh receptor

Kinase-linked
receptors

Receptors linked to
gene transcription
(nuclear receptor)

minutes

hours

Insulin
receptor

Estrogen
receptor

Ions in the extracellular


environment

DRUG
Receptor

Happens in a matter or

MILLISECONDS

Inotropic

Drug binding causes the


channel to open allowing
Ions to enter, resulting to either
HYPERPOLARIZATION or
DEPOLARIZATION

Ion channels
Activation generates action potentials
EPSP (excitatory post synaptic potentials) are
initiated when excitatory neurotransmitter activates
Na+ or Ca+2 channels
IPSP (inhibitory post synaptic potentials) are
initiated when an inhibitory neurotransmitter open
Cl and K+ channels and membrane becomes
hyperpolarized

Ion Channels
Ligand gated or receptor operated ion channel (ROC)
activated when a drug or an endogenous substance
(neurotransmitter) binds with a specific receptor
thus increasing transmembrane conductance of the
relevant ion and thereby altering the electrical
potential across the membrane
VOC when a drug or an endogenous substance
(neurotransmitter) do not bind directly but are
activated by membrane potential

Ligand binds to its


receptor

RECEPTOR

The , , & subunit is known

as the G-PROTEIN

G-Protein(Second
Messenger)

GDP Molecule
The binding caused
a phosphorylation
to the GDP, making
it to GTP (Active)

RECEPTOR

G-Protein(Second
Messenger)

GTP

G-protein binds to adenylyl


cyclase, ACTIVATING it.
cAMP

cAMP is responsible for an


array of cellular effects

ATP
ATP will be processed
by adenylyl cyclase
and be converted to:

2 Phosphate molecules

G-Protein(Second
Messenger)

GTP

subunit-GTP complex (G-protein)


goes to the cytoplasm in search of the
ADENYLYL CYCLASE

GTP

After a while, the G-Protein is


converted back to inactive
state ( subunit-GDP)
The adenylyl cyclase will be
inactivated

G-Protein(Second
Messenger)

The subunit-GDP will be


recycled back.

RECEPTOR

G-Protein(Second
Messenger)

Types of G-Protein Coupled Receptors

Gi inhibit
adenylyl cyclase

Gs activate
adenylyl cyclase

Gq activate
Phospholipase C

SECOND MESSENGER SYSTEMS


Are systems that allow signals from cell
surface receptors to be converted and amplified
into a cellular response.
I. cAMP produced by adenylate cyclase
II. cGMP produced by guanylate cyclase
III. IP3, DAG produced by phospholipase C

Biological actions of cAMP


Activation of phosphorylase kinase and
conversion of inactive phosphorylase to
active phosphorylase which results in:
Lipolysis
Reduced glycogen synthesis
Increased glycogen breakdown

Activation of L-type Ca2+ channels and


sarcoplasmic reticulum in cardiac cells by
phosphorylation, so
increasing Ca2+ currents and release

Biological actions of IP3


To facilitate the entry of Ca2+ into different cellular
compartments
Smooth muscle contraction
Increased rate of contraction and relaxation of
cardiac myocytes
Secretion of transmitter molecules or glandular
secretions
Hormone release
Cytotoxicity
Activation of certain enzymes

Biological actions of DAG


Influences the activity of membrane-bound protein
kinase C
Modulation of the release of endocrine
hormones and neurotransmitters
Smooth muscle contraction
Inflammation
Ion transport
Tumor promotion

RECEPTOR
(i.e. Insulin)

RECEPTOR

ATP

ATP will cause


phosphorylation

tyr

tyr

tyr

tyr

tyr

tyr

Activated
Proteins

Intracellular Enzymatic Domain


TYROSINE KINASE

ATP will be converted to ADP & the phosphate group


will activate the tyrosine kinase

Kinase Linked Receptors

CELLULAR EFFECTS!!!

Carrier Molecules
Energy-independent carriers
Energy-dependent pumps
Uniporters
Symporters
Antiporters

Uniporter

Transport proteins that transport a substance from


one side of the membrane to the other

Symporters
are transport proteins that simultaneously transport two
substances across the membrane in the same direction

Antiporters
are transport proteins that transport one substance across the
membrane in one direction while simultaneously transporting a
second substance across the membrane in the opposite
direction e.g. Na+/Ca2+- exchanger

TYPES OF DRUG INTERACTION


ADDITION

The response elicited by combined drugs is EQUAL to the


combined responses of the individual drugs (1 + 1 = 2)

SYNERGISM

The response elicited by combined drugs is GREATER than


the combined responses of the individual drugs ( 1 + 1 = 3)

POTENTIATION

A drug which has no effect on the system enhances the


effect of the other (0 + 1 = 2)

ANTAGONISM

Drug inhibits the effect of another due to opposite


pharmacological actions (1 + 1 = 0)

DOSE-RESPONSE RELATIONSHIP
GRADED RESPONSE
It is characterized by the
magnitude of resistance
increasing continuously with
greater concentration of
unbound drug at the
receptor site

Criteria for drug selection and determining


appropriate doses of drug
POTENCY
Refers to the concentration
(EC50) or dose (ED50) of a drug
required to produce 50%of that
drugs maximal response

EFFICACY
The relationship between
receptor occupancy and its
ability to initiate a response
Graded dose-response curve
indicates maximal efficacy of a
drug
A.k.a. Intrinsic Activity
Measured by Emax

100%

Emax

50%

0%

ED50
0

0.1

0.2

0.3

0.4

Describes how strong a


drug BINDS to its
receptor

AGONIST

Describes HOW GOOD


the response to the
drug is.

Initiate cell function producing effects of


various types
Potency depends on; affinity and efficacy
Full agonist (high efficacy)
Partial agonist (intermediate efficacy)
* Potency refers to the relative concentration required to produce a given
magnitude of effect

Types of Drug-Receptor Interactions: Agonists


100%

PERCENT MAXIMUM RESPONSE

Full Agonist
Full agonist gives
100% efficacy
50%

Partial Agonist
Partial agonist gives less
than 100% efficacy
0%
0

0.1

0.2
DOSE

0.3

0.4

ANTAGONIST
Bind to receptor without initiating changes
Efficacy is zero
Inhibits or blocks responses caused by agonist

TYPES OF DRUG ANTAGONISM


COMPETITIVE ANTAGONISM
Equilibrium competitive or reversible
Nonequilibrium competitive or irreversible

NONCOMPETITIVE ANTAGONISM
PHARMACOKINETIC ANTAGONISM
CHEMICAL ANTAGONISM
PHYSIOLOGICAL ANTAGONISM

Competitive antagonism

Types of Drug-Receptor Interactions: Antagonist


100%

PERCENT MAXIMUM RESPONSE

Agonist Alone

50%

Higher dose of agonist +


Reversible antagonist

Rightward Shift

Agonist + Reversible
Antagonist

Effects decrease
But if the dose of the agonist is
increased, its effects would be restored

0%
0

0.1

Lowers POTENCY but not EFFICACY

0.2
DOSE

0.3

0.4

Equilibrium Competitive (reversible) Antagonists


Bind reversibly to receptors at the
same site as the agonist
Competitively prevent the agonist
from binding to the receptor
causing a blockade of effects
Graphically observed as a
rightward
shift of the dose-response
curve
Effects can be overcome by adding
higher concentrations of the
agonist
Lower potency but have no effect
on efficacy because they
produce the same maximum
response as agonist alone

Types of Drug-Receptor Interactions: Antagonist


100%

PERCENT MAXIMUM RESPONSE

Agonist Alone

50%

Higher dose of agonist +


Irreversible antagonist

Downward Shift

Agonist + Irreversible
Antagonist

Effects decrease
Even if the dose of the agonist is increased, its
effects would still be reduced

0%
0

0.1

Lowers EFFICACY but not POTENCY

0.2
DOSE

0.3

0.4

Non-equilibrium Competitive (irreversible) Antagonists


Bind irreversibly to either the same
site as the agonist or to an
alternative site thus, causing
blockade of the effects of the
agonists
Graphically observed as a
downward shift of the doseresponse curve with no
potential for achieving
maximum response
Increasing concentrations of the
agonist has no effect since
interaction is irreversible
and bound drug are no
longer available for
activation
Lowers the efficacy, but has no
effect on potency

Non-Competitive
antagonism

Noncompetitive Antagonism
The antagonist acts at a site beyond the receptor
for the agonist
Antagonizes agonists acting through more than
one receptor system (e.g., diazoxide)

Pharmacokinetic
antagonism

PHARMACOKINETIC ANTAGONISM
Antagonist effectively reduces the
concentration of the active drug at its site of
action
Example: Phenobarbital reduces anticoagulant
effect of warfarin by accelerating its
metabolism

Chemical antagonism

CHEMICAL ANTAGONISM
Neutralization
Two substances combine in solution, so that
the effect of the active drug is lost
Example: Dimercaprol chelates heavy metals
and thus reduce their toxicity

Physiologic antagonism

PHYSIOLOGICAL ANTAGONISM
Interaction of two drugs whose opposing actions in
the body tend to cancel each other
It describes the ability of an agonist (rather than an
antagonist) to inhibit the response to a second agonist
via activation of different receptors that are physically
separate
Example: Histamine stimulates GI acid secretion, while
Omeprazole inhibits proton pump thus blocking this
effect

QUANTAL DOSE RESPONSE RELATIONSHIP


Graphically plots the percent of the
population that responds to a drug versus the
drug dose
QUANTAL RESPONSE
The observable response can be described only in
terms of an all or none event.

QUANTAL DOSE EFFECT CURVE


Often characterized by stating the;
MEDIAN EFFECTIVE DOSE (ED50)
The dose at which 50% of the individual exhibit
the specified quantal effect

MEDIAN TOXIC DOSE (TD50)


The dose required to produce a particular toxic
effect in 50% of animals

MEDIAN LETHAL DOSE (LD50)


The dose with which the toxic effect is death to
50% of the population

Drugs with opposing effect

Drugs with similar effect

Displacement
from protein
binding site

Drug
Interactions

Alteration
of absorption

Inhibitors
or facilitator
of excretion
Changes
in
metabolism

Alteration of
electrolyte levels

Alteration of GI flora

Toxic reactions
Is the degree or extent to which a drug can be poisonous
and thus harmful to the human body
Is injury or death produced by any substance when it is
absorbed by a living organism
Classes

Dose related toxicity


Drug-induced diseases
Idiosyncratic reactions
Allergic related reactions

Dose-related Toxicity
May result from the local accumulation of a drug or drug
overdose thus, toxic levels may build up before enough
drug is eliminated to reach steady state in the
therapeutic range

Drug-induced Diseases
Toxicity causing damage to tissues and organs which may
either be reversible or irreversible depending on the
toxicity and the tissues or organs involved

Idiosyncratic Reactions
An unexpected reaction to a drug which is a result of a
genetically determined abnormality

Allergic Reactions
An antigen-antibody reaction
An adverse reaction that results from previous
exposure or sensitization to a particular drug
It is not a result of the pharmacologic effects of
drug but rather, is a result of patients immune
system, which identifies the drug as foreign
substance that must be neutralized or
destroyed

End of the Introduction to


Pharmacology

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