Pharmacodynamics

dr. Bayu Lestari

Pharmacology Laboratory
Medical Faculty of Brawijaya University
Case 1
Ana, 19 y.o suffered from urticaria after
meal (seafood). She take chlorpeniramine
maleat (CTM) for her allergy. After take
this drug, she get better for her itchy skin,
but she feel sleepy, dry mouth, and slight
dizziness. How do you explain side effects?
Case 2
Catherine, 25 yo, suffered from nausea n
epigastric since 1 day ago. She had took
antasida syrup for her abdominal pain, but
there was no relief. She go to the doctor
and got omeprazole for her complaint. She
fell better after take omeprazole two times
daily before meal. How does antasida work?
What is the differences with omeprazole?
Case 3
Antok, 35 yo, suffered from myalgia and arthralgia since 3 days ago.
He immediately go to public health care. The doctor give him
methampyrone (antalgin) for his complaint. 30 minutes after he take
this drug, he feel dizziness. From physical examination his blood
pressure dropped into 80/60, tachycardia 120x/min, and cold
extremities. Doctor had been diagnosed him with anaphylactic shock
and perform resuscitation immediately.
How does Drug Act?
Pharmacokinetics vs Pharmacodynamics
Principle
Drugs dont create new effect, but altered physiological response

Every drugs have side effect when it administered, even herbs

No drugs cause single and specific effect

Definition
Study of the biochemical and physiological effects of
drugs and their mechanisms of action

Rational therapeutic
Drug design
drugs
Mechanism of Drug Action
Mostly drugs interact with macromolecular components
of organism defined as RECEPTOR

RECEPTOR mostly proteins

Some drugs dont bind to its RECEPTOR

Protein as Drug Receptor

Receptor for hormones, growth factor, transcription factor,

and neurotransmitter
Receptor for enzymes of crucial metabolic or regulatory
pathways
Protein involved in transport process, secreted
glycoproteins, structural protein
Nucleic acid as drug receptor in cancer chemotherapeutic
agents
DrugReceptor Interaction

Drugs

AFFINITY Interaction: ionic, hydrogen, hydrophobic, van der Walls, and covalent

Altered Biological Response Intrinsic Activity EFFICACY

Drug-Receptor Interactions
Drug-Receptor Interactions
Drug-Receptor Interactions
Some receptor in inactivated form (Ri) &
other in activated form (Ra)
Some Ra cause intrinsic activation without
agonist binding constitutive activity

Full Agonist: bind to Ra, maximal response

Partial Agonist: bind to Ra, partial response

Antagonist: bind to Ra and Ri, but no response

Inverse Agonist: bind to Ri > Ra, decrease

response
Non-Receptor Drug Action
Antasida
Antibiotics
Normal saline for resuscitation
Agents used for constipation (stimulate water secretion), etc
Receptor Type
Ligand-Gated Ion Channels
G-Protein Coupled Receptor
Kinase-Linked Receptor
Intracellular Receptor
Ligand-Gated Ion Channels
Structure of nicotinic receptor consists of 5 subunit

Ach (acetylcholine) binds to subunit

Channels opening

Sodium influx

Depolarization of neurons

RESPONSE

Other examples: GABA receptor, serotonin (5-HT) receptor,

glycine receptor, etc.
Diazepam

Used for anti-anxiety, insomnia

Allosteric activator of GABA receptor
Mediates Cl- influx
Inverse agonist cause agitation and anxiety
G-Protein Coupled Receptor
GPCR located at plasma
membrane as a bundle of
seven helices
G-protein consist of 3
subunit (, , and )
-subunit is activated when
it bind GTP
-subunit activates effector
protein
and could directly
activate K+ channels
Consist of many subtype:
Gs, Gi, Gq, Golf, Gt
G-Protein Coupled Receptor Agonist-receptor binding

Activation of G-Protein

-subunit exchange GDPGTP

Alteration of Effector Protein

Adenylate cyclase
(ATPcAMP)
Phospholipase C (PLC) (PIP2
IP3 + DAG)
Ion channel protein

Cellular Response
G-Protein Coupled Receptor
Norepinephrine (1 Agonist)
Stimulation GPCR in cardiac
myocyte caused increase of
contractility
NE bind to GPCR activate
Gs activate adenylate
cyclase increase of cAMP
level activate PKA
release of calcium from its
storage (sarcoplasmic
reticulum) and increase
influx of calcium
contraction
Effect on SA node
tachycardia, Renal renin
release, hepar
glycogenolysis
Salbutamol (2 agonist)

Stimulation GPCR in lung

smooth muscle caused
bronchodilatation
Salbutamol bind to GPCR
activate Gs activate
adenylate cyclase
increase of cAMP level
inhibition of MLC (myosine
light chain) kinase
relaxation
GPCR, G-Protein, and Their Effectors
 Tyrosine Kinase

Binding of ligand

Dimerization of receptor

Phosphorylation of receptor

Activate downstream signaling

RESPONSE

Example: Insulin Receptor (IR), epidermal growth factor (EGF), platelet-derived

growth factor (PDGF), atrial natriuretic peptide (ANP), transforming
growth factor- (TGF-), and many other trophic hormones
Intracellular Receptor
Ligand translocate to cytoplasmic receptor

Binding of ligand-cytoplasmic
receptor
Homodimeric/ heterodimeric
receptor translocate to nucleus

Regulate gene expression

RESPONSE
What is the Type of This Receptor?
Graded-Dose Response

Concentration- Log [Concentration]-Response

Response
EC50 reflects effective concentration needed for
50% response, efficacy has continuous scale
Quantifying Agonism

Relative potency reflects EC50 of Relative efficacy reflects maximal

drugs compared with other drugs/ response of drugs compared with
substances other drugs/ substances
Describe this Picture
Drug-Receptor Interactions
Agonist: bind to receptor at the same site of
endogenous substance intrinsic activation
Competitive inhibitor: bind to receptor at the same site
of endogenous substance no intrinsic activation
Allosteric activator: bind to receptor at the other site
of endogenous substance intrinsic activation
Allosteric inhibitor: bind to receptor at the other site of
endogenous substance no intrinsic activation
Quantifying Antagonism

Agonist + Competitive Antagonist decrease POTENCY

Isoprenaline (Agonist) + Propanolol (Comp.
Antagonist) in Guinea Pig Atria
Quantifying Antagonism

Agonist + Allosteric Antagonist decrease EFFICACY

5-HT (Ag) + Methysergide (Allosteric
Antagonist) in Rat Stomach Smooth Muscle
Quantifying Antagonism

Agonist + Pseudo-Irreversible Antagonist decrease EFFICACY and

POTENCY
Carbachol (Ag) + Dibenamine (Pseudo-
Irreversible Ant) in Rabbit Stomach
Describe this Picture
Quantal Dose
Response Curve
All or none (death or alive,
pain or no pain, effective or
not)
Performed in population
Determine ED50 and LD50
Determine therapeutic
index
Therapeutic Index
Area between effective
dose and lethal dose
Wide range reflect safer
drugs, narrow range reflect
less safer drugs
Formula of TR (Therapeutic
Ratio) = LD50/ED50 (animal)
or TD50/ED50 (human)
Receptor Regulation
Upregulation
Prolonged exposure of
antagonist
Cause hyperreactivity
Downregulation
Prolonged exposure by
agonist
Cause tolerance/
hyporeactivity
Receptor regulation:
Homolog
Heterolog
GPCR Homologues Down-Regulation
-arrestin bind to GPCR

Activate GPCR internalization

GPCR degraded by lysosome

GPCR recycled
Variation of Drug Response
Tolerance (same dose, less response)/ hyporeactive
Decrease the number of receptor
Decrease downstream signaling
Decrease sensitivity of receptor
Rapid tolerance termed as tachyphylaxis
Hyperreactivity (same dose, more response)
Increase the number of receptor
Increase sensitivity of receptor
Different with term hypersensitivity
Variation of Drug Response
Idiosyncration
Caused by genetic differences in metabolism of the drug or by immunologic
mechanisms
Example: allergic reactions, anaphylactic shock, delayed typed
hypersensitivity (Steven-Johnson syndrome)
Variation of drug response caused by:
Alteration of drug concentration that reach receptor
Variation concentration of endogenous ligand
Alteration of number or function of receptor
Changes in components distal to receptor
Drug Allergy
Side Effects vs Toxic Effect
Toxic effects occurred
when administered
drugs in higher/ toxic
dose
Side effects occurred
when administered
drugs in therapeutic
dose
Side Effect vs Toxic Effect
Selectivity of Drugs
Case Study
A 51-year-old man presents to his medical clinic due to difficulty
breathing. The patient is afebrile and normotensive, but tachypneic.
Auscultation of the chest reveals diffuse wheezes. The physician
provisionally makes the diagnosis of bronchial asthma and administers
epinephrine (non selective and adrenoceptor agonist) by
intramuscular injection, improving the patients breathing over several
minutes. A normal chest X-ray is subsequently obtained, and the
medical history is remarkable only for mild hypertension that was
recently treated with propranolol ( adrenoceptor antagonist). How do
you explain this case?