PREPARED BY: REYSAN S.

COSAS
• Pharmacodynamics (PD) is the division of Pharmacology that
describes the action of drugs.
• It includes the measurement of responses to drugs and how
response relates to drug dose or concentration.
• Simply, the term answers the question, "what the drug does to
the body"?
• STIMULATION - drugs may increase or enhance the function
of an organ or a system.
• DEPRESSION - drugs inhibit or decrease the function of an
organ or the system.
• IRRITATION - this is an action attributed to the local effects
of the drug on a tissue or cell.
• OTHERS
• Replacing deficiency of an essential chemical - action of vitamins,
minerals, or other supplements; or,
• Killing/Weakening invading microorganism/rapidly proliferating cells -
action of antiinfectives and antineoplastics
• PRIMARY - intended; it is usually the desired effect that leads
to its therapeutic use

• SECONDARY - is unintended; commonly leading to undesired

effects
1. Structural nonspecific
• Alter the cell environment by physical or chemical processes

2. Structural specific
• Alter cell function by drug-receptor interactions
• The majority of drugs' action is through this mechanism
MECHANISM DEFINITION RESPONSE COMPONENTS

Interaction with drug’s molecular The drug target (receptor, ion channel, enzyme,
Molecular
target carrier molecule

The biochemicals linked to drug target (ion

Cellular Transduction
channel, enzyme G protein)

Electrogenesis, contraction secretion, metabolic

Tissue An effect on tissue function
activity, proliferation

Integrated systems including linked systems (e.g.

System An effect on system function
NS, CVS)
• Langley and Erlich first proposed that drug actions were
mediated by chemical RECEPTORS.

• Any target molecule with which a drug molecule has to combine

in order to elicit its specific effect

• It is the component of a cell or organism that interacts with a

drug and initiates the chain of events leading to the drug's
observed effects.
Ligand refers to any molecule which attaches selectively to
particular receptors or sites

• AFFINITY - is the capacity of a drug to form the complex with

its receptor (DR complex), e.g., the key entering the hole of the
lock has got an affinity to its levers

• INTRINSIC ACTIVITY (OR) EFFICACY - it is the ability of

a drug to trigger the pharmacological response after making the
drug-receptor complex
• AGONIST - refers to an agent that activates a receptor to
produce an effect similar to that of the physiologic signal
molecule. It has both high affinity as well as high intrinsic
activity, therefore can trigger the maximal biological response

• PARTIAL AGONIST - an agent that activates a receptor to

produce a submaximal effect but antagonizes the actions of a
full agonist. It has full affinity but with low intrinsic activity and
hence is only partly as effective as an agonist.
• INVERSE AGONIST - decreases the number of activated
receptors to below that observed in the absence of drug. Thus,
inverse agonists have an intrinsic activity less than zero, reverse
the activity of receptors, and exert the opposite pharmacological
effect of agonists.

• ANTAGONIST - an agent that prevents the action of an

agonist on a receptor but doesn’t have any effect of its own. It
has only affinity but no intrinsic activity. This drug binds to the
receptor and blocks the binding of an endogenous agonist.
• Receptors largely determine the quantitative relations between
dose or concentration of drug and pharmacologic effects

• Receptors are responsible for the selectivity of drug action

• Receptors mediate the actions of pharmacologic agonists and

antagonists
• “ORPHAN” RECEPTOR - so-called because their ligands are
presently unknown, which may prove to be useful targets for the
development of new drugs

• REGULATORY PROTEINS - the best-characterized receptors;

modify the actions of endogenous chemical signals
(neurotransmitters, autacoids, hormones)

• Other proteins identified as DRUG RECEPTORS

• Enzymes - may be inhibited (or less commonly activated) by binding a drug.
Example: dihydrofolate reductase, the receptor for methotrexate
• Transport proteins - Example: Na+, K+ ATPase – receptor for digoxin
• Structural proteins - Example is Tubulin, the receptor for colchicine
 THEIR TRANSDUCTION
COMPONENTS AND MECHANISMS
Type I receptors
• Also known as channel-linked, and ionotropic receptors
• 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
• The natural ligands of such receptors include acetylcholine,
serotonin, GABA, and glutamate.
• Examples are nicotinic, 5-HT, GABA and NMDA receptors
Type I receptors
• 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
• Voltage gated ion channel (VOC) – when a drug or an
endogenous substance (neurotransmitter) do not bind directly
but are activated by membrane potential
Type II receptors
• Also known as G-protein coupled, “seven-transmembrane” or
“serpentine”, and metabotropic receptors
• The activated effectors produce second messengers that further
activate other effectors in the cell, causing a signal cascade
effect.
• Examples are muscarinic, alpha, beta, dopaminergic, glucagon
receptors, thyrotropin receptors.
Types of G-protein and Second Messenger Systems

Gi inhibit Gs activate Gq activate

adenylyl cyclase adenylyl cyclase 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 adenylyl cyclase

II. cGMP – produced by guanylyl cyclase
III.IP3, DAG – produced by phospholipase C
Second Messenger Systems
Biological actions of cAMP

• It exerts most of its effects by stimulating cAMP-dependent

protein kinase A:
• Mobilization of stored energy
• Conservation of water by the kidney
• Calcium homeostasis
• Increased rate and contractile force of heart muscle
• Regulate the production of adrenal and sex steroids
• Relaxation of smooth muscle, and many other endocrine and neural
processes
Second Messenger Systems
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
Second Messenger Systems
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
Second Messenger Systems
Biological actions of cGMP

• It has established signaling roles in only a few cell types.

• It acts by stimulating a cGMP-dependent protein kinase.
• Relaxation of vascular smooth muscle by a kinase-mediated
mechanism that results in dephosphorylation of myosin light chains
Type III receptors
• Also known as enzyme-linked receptors
• This response lasts on the order of minutes to hours.
• The most common enzyme-linked receptors (epidermal growth
factor, platelet-derived growth factor, atrial natriuretic peptide,
insulin, and others) possess tyrosine kinase activity as part of
their structure.
Type IV receptors
• Also known as nuclear or intracellular receptors. The ligand
must diffuse into the cell to interact with the receptor.
• The primary targets of these ligand–receptor complexes are
transcription factors in the cell nucleus.
• The time course of activation and response of these receptors is
on the order of hours to days.
• Example is hormonal receptors (estrogen receptors)
ANTAGONIST
• An antagonist has no effect in the absence of an agonist but can
decrease the effect of an agonist when present.
• Bind to receptor without initiating changes
• Efficacy is zero
• Inhibits or blocks responses caused by agonist
Antagonism: Based on MOA
• Chemical antagonism – antagonist neutralizes the effect of
agonist (e.g. neutralization reaction, chelation of heavy metals)

• Physiologic antagonism – antagonist may act at a completely

separate receptor, initiating effects that are functionally
opposite those of the agonist

• Pharmacologic antagonism – antagonist acts at a similar

receptor causing competitive antagonism
Antagonism: Based on surmountability
• Competitive (surmountable) antagonism – both agonist &
antagonist compete with the same active site in the receptor
causing prevention of an agonist from binding to its receptor

• Non-competitive (non-surmountable) antagonism – antagonist

acts at a site beyond the active site of the agonist’s receptor
Antagonism: Based on bond interaction
• Reversible antagonism – forms non-covalent bond specifically
intermolecular forces of interaction

• Irreversible antagonism – binds covalently to the active site of

the receptor, thereby reducing the number of receptors available
to the agonist.
 100%

Agonist Alone

PERCENT MAXIMUM RESPONSE

50% Higher dose of agonist

+ Reversible antagonist

“Rightward Shift”
Agonist + Reversible
Antagonist
Effects decrease
But if the dose of the agonist is increased,
it’s effects would be restored
0%
0 0.1 0.2 0.3 0.4
Lowers POTENCY but not EFFICACY DOSE
Reversible Antagonists

ü Bind reversibly to receptors at the

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

it’s effects would still be reduced
0%
0 0.1 0.2 0.3 0.4
Lowers EFFICACY but not POTENCY DOSE
 Irreversible Antagonists

ü Bind irreversibly to either the same

site as the agonist or to an alternative
site thus, causing blockade of the
effects of the agonists
ü Graphically observed as a downward
shift of the dose- response curve with
no potential for achieving maximum
response
ü Increasing concentrations of the
agonist has no effect since interaction
is irreversible and bound drug are no
longer available for activation
ü Lowers the efficacy, but has no effect
on potency
Pharmacodynamic Drug Interaction by
Enhancement of drug effect
• 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)
Dose-Response Relationships
• Graded Dose-Response Relationship
• Quantal Dose-Response Relationship
 GRADED DOSE-RESPONSE
RELATIONSHIP
• It plots the magnitude of
response against increasing
doses of a drug
• It is characterized by the
magnitude of response
increasing continuously with
greater concentration of
unbound drug at the receptor
site.
 GRADED DOSE-RESPONSE
RELATIONSHIP
POTENCY 100%
ü Refers to the concentration (EC50)
or dose (ED50) of a drug required Emax
to produce 50%of that drug’s
maximal response
EFFICACY 50%
ü The relationship between receptor
occupancy and its ability to initiate
a response
ü Graded dose-response curve
indicates maximal efficacy of a drug ED50
ü “Intrinsic Activity” 0%
0 0.1 0.2 0.3 0.4
ü Measured by Emax
 QUANTAL DOSE RESPONSE
RELATIONSHIP

• Graphically plots the percent of the

population that responds to a drug
versus the drug dose
• Used to generate information
regarding the margin of safety to be
expected from a particular drug used to
produce a specified effect.
• QUANTAL RESPONSE
• The observable response can be described
only in terms of an all or none event.
 QUANTAL DOSE RESPONSE
RELATIONSHIP
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
 QUANTAL DOSE RESPONSE
RELATIONSHIP

• Therapeutic index (TI) of a drug is the ratio of the dose that

produces toxicity in half the population to the dose that
produces a clinically desired or effective response in half the
population

• TI is a measure of a drug’s safety (margin of safety)

• A larger value indicates a wide margin between doses that are effective
and doses that are toxic
SPECIAL PHARMACOLOGICAL
RESPONSES

• Hypereactive
• A drug produces usual effect at unexpected low dosage
• Supersensitivity
• A drug produces increased sensitivity as a result of denervation
• Hyporeactive
• A drug produces usual effect at unexpected high dosage
SPECIAL PHARMACOLOGICAL
RESPONSES
• Tolerance
• A decrease in the sensitivity acquired as a result of prior exposure to the
drug, thus, decrease pharmacologic effect.
• Desensitization/Tachyphylaxis
• Rapid development of tolerance after administration of few doses of
drug
• Immunologic (allergic/hypersensitivity) reactions
• A result of patient’s immune system, which identifies the drug as
foreign substance (antigen) that must be neutralized or destroyed
SPECIAL PHARMACOLOGICAL
RESPONSES

• Idiosyncratic reactions
• A genetically-determined reaction that results to unwanted effect that is
beyond the drug’s pharmacology
• Placebo reactions
• A psychological reaction from taking a substance with no intrinsic
pharmacologic activity but may yield therapeutic outcome.