Pharmacodynamics

What the Drug Does to the

Body
Setyawati S Karyono
Laboratorium Farmakologi
Fakultas Kedokteran Unibraw

Basic Pharmacological Concepts

Pharmacology = The study of the interaction

between chemicals and a biological system.

Pharmacodynamics = study of the biochemical and

physiological effects of drugs and their mechanisms
of action (the effects of the drug on the body)

Pharmacokinetics = deals with absorption,

distribution, biotransformation and excretion of drugs
(the way the body affects the drug with time)

LOCUS OF ACTION
RECEPTORS

Bound

ABSORPTION

Free

TISSUE
RESERVOIRS

Free

Bound

Free Drug
Bound Drug

SYSTEMIC
CIRCULATION

BIOTRANSFORMATION

EXCRETION

Pharmacodynamics
Mechanisms of drug action

Non-specific drug action

general anaesthetics, osmotic diuretics, antacids
Alter transport systems
Ca antagonists, local anaesthetics, cardiac
glycosides
Alter enzyme function
COX inhibitors, MAO inhibitors, AChE inhibitors
Act on receptors
Synaptic transmitter substances, hormones

Langley (1905)

Receptive substance

Nicotin

Electrical stimulation

(-) CURARE
Skeltal muscl.
contraction

Ehrlich (1913)

Skeltal muscl.
contraction

specificity of the chemical

structure
receptor structure
corpora non agunt nisi fixata

Site of Drug Action

The part of the body (organ, tissue, cell type)

where a drug acts to initiate the chain of
events leading to an effect.

Example: systemic morphine induces

pupillary miosis, but not due to direct action
on iris muscle.

Also, drugs may have different effects in the

same tissue...

Receptor

The macromolecular (protein) complex with which

drugs interact to elicit their characteristic biological
effects.

Drug receptors for endogenous ligands (hormones,

neurotransmitters)

Drug actions receptor-selectivity & tissue-specificity

Structure-Activity Relationship: the relationship

between the chemical structure of a drug and its
biological effect.

Classical Receptors

Span the membrane.

Amphipathic (polar and nonpolar regions).

alpha-helices form the nonpolar transmembrane

regions.

Polar

Nonpolar

Polar

Characteristics of DrugReceptor Interactions

Chemical Bond: covalent, ionic,

hydrogen, hydrophobic, and Van der
Waals.
Competitive, agonist-antagonist
Specific and Selective
Structure-activity relationships
Transduction mechanisms

DRUG RECEPTOR INTERACTIONS

Intermolecular forces

Covalent bonds - two atoms share an electron

-

(40-110kcal/mol) - long lasting

- desirable?

e.g. Alkylating agents (e.g. anticancer nitrogen mustards)

Ionic bonds - electrostatic attraction between

oppositely charged ions
-

much weaker than covalent bonds (10 kcal/mol)

reversible

Hydrogen bonds - electrostatic attraction between

hydrogen atom and electronegative atom
-

relatively stable (1-7 kcal/mol)

Van der Waals bond

- reversible

- weak bond (0.5 - 1 kcal/mol)

Drug-receptor interaction

Classification Receptor
1.
2.

3.
4.

Transduction
Mechanisms
Ion channel linked receptors e.g. Ach
nicotinic (Na+) and GABA (Cl-)
Second messenger generation,
adenylate cyclase stimulation or inhibition cAMP,
guanylate cyclase - cGMP, phospholipase C IP3,DAG
Some receptors are themselves protein
kinases
Intracellular receptors (e.g. corticosteroids,
thyroid hormone)

Transmembrane Signaling
Mechanisms
= drug

Out

In

Y
P

gene

Transmembrane Actions

Drugs acting at the cell membrane produce

transmembrane signals by regulating one or more
of the following:

Ligand-gated ion channels.

G proteins and second messengers.

Transmembrane enzymes

1:
1: Ligand-gated
Ligand-gated Ion
Ion Channels
Channels

Neurotransmitters GABA (A-type), ACh (nic),

5-HT (5-HT3), and EAAs (e.g., glu) bind in part
to ligand-gated channels.

Increased membrane conductance occurs by

the opening of gated channels for specific
ions (Na+, K+, Ca2+), which then follow their
electrochemical gradients.

Examples: cartoon illustrations.

GABAA Receptor:
chloride channel

Channel pore

2:
Membrane Receptors
Receptors Associated
Associated With
With
2: Membrane
G
G Proteins,
Proteins, an
an Effector,
Effector, and
and Diffusible
Diffusible
Second
Second Messengers:
Messengers: GPCRs.
GPCRs.

G proteins are inactive when GDP is bound and

active when GTP is bound.

G proteins consist of an , a , and a subunit.

The subunit interacts with the activated
receptor, with GDP/GTP, and with the effector
enzyme (or channel).

Types of G proteins: Gs, Gi, Go, Gq

Schematic of a G Protein-Linked
Receptor

extracellular
NH2

Ligand binds here

7 transmembrane
segments

Plasma
Membrane

intracellular

Gs
binds here: 3rd
Intracellular loop

COOH

AC / cAMP System

Receptor

The chemical message is transduced across the

cell membrane in four stages.
1)

Binding of drug (i.e., ligand) to

receptor.

2)

Receptor activation of a G protein.

3)

G protein regulation of an enzyme or

ion channel.

4)

Change in the concentration of a

second messenger.

Binding of drug to receptor

receptors

Change in the
Receptor activation cons.of second
messenger
of a G protein

G prot regulation
of an enzyme or
ion channel

Inactivation
mechanism

Stage 1

Stage 2

Stage 3

Stage 4

Mechanism of beta-1 receptor activation in

cardiac muscle

Effect of beta-2 receptor activation

on smooth muscle

The Major Effectors and Intracellular

Second Messengers in GPCR Systems
2nd messenger

Effector

adenylyl cyclase

cyclic AMP (cAMP)

phospholipase C

calcium, DAG, and

phosphoinositide (IP3)

Calcium-Phosphoinositide Second
Messenger System
G protein-linked.
Activation of phospholipase C results in
hydrolysis of phosphotidylinositol-4,5bisphosphate (PIP2) into two second
messengers, diacylglycerol (DAG) and
inositol-1,4,5-triphosphate (IP3).
DAG activates protein kinase C.
IP3 mobilizes stored intracellular calcium.

The Ca2+-Phosphoinositide Signaling

Pathway
Rec

cytoplasm

PLC
PIP2
IP3

PKC
ATP

Ca2+

CaM

membrane

DAG
+

Substrate

CaM-E*

Response

ADP

Sub-P

Mechanism of alpha-1 receptor activation

of smooth muscle contraction

3: Ligand-regulated
Ligand-regulated Transmembrane
Transmembrane
Enzymes
Enzymes (tyr
(tyr Kinases)
Kinases)
1)

Drug or hormone binds extracellular domain.

2)

Allosteric effect autophosphorylation of

intracellular domain.

3)

Phosphorylated form phosphorylates substrate

proteins.

Agonists: insulin, EGF, other growth factors

 Linked directly to tyrosine kinase

Receptor acts as an enzyme

receptors

EGF Receptor
Active dimer

Inactive monomer form

4:
4: Intracellular
Intracellular Actions:
Actions:
Regulation
Regulation of
of Gene
Gene Transcription
Transcription

Cytosolic receptors. Steroid hormones cross the cell

membrane and bind cytosolic receptors. The
complex is transported to the nucleus and binds DNA
sequences near the gene whose expression is to be
regulated.

Nuclear receptors. Thyroid hormone enters the cell

and passively enters nucleus to bind its receptor
(part of chromatin).

Intracellular Mechanism: Steroid

Nucleus
XXXXXXXXXXXXX

Effects
Protein

Plasma

RNA
mRNA

drug

 Nuclear
receptors that
regulate
gene
transcription

receptors

Speed of responses

DRUG - Agonis
- Antagonis

Agonists

Agonists: produce effects similar to those

produced by naturally occurring hormones,
neurotransmitters and other substances
Example: beta agonists stimulate beta
cells (B2) in the lungs causing relaxation of
the bronchial smooth muscles. (Albuterol,
Alupent inhalers)

Antagonists

Antagonists: inhibit cell functions by

occupying receptor sites. Prevent natural
body substances or other drugs from
occupying receptor sites and activating cell
functions
Example: beta antagonists (beta blockers)
occupy beta sites throughout the body
causing slowing of the pulse, decrease
blood pressure and decreased cardiac
output. (Atenolol, Timolol)

Agonist vs antagonist
Ag

Ant

K+1
R

K-1

Ag

K+1

R
K-1

Ant

Response

Agonist & Antagonist

Agonist & Antagonist