PHARMACODYNAMIC

NURLAILI SUSANTI

L A B O R AT O RY O F P H A R M A C O L O G Y
M E D I C A L D E PA R T M E N T
F A C U LT Y O F M E D I C I N E A N D H E A LT H S C I E N C E
PHARMACODYNAMIC
The action of a drug on the body to produce biological effect
How drugs work on the body
MECHANISM OF DRUG ACTION
• An understanding of the mechanism of action of drugs is the basis for
determining the rational therapies of a new drug and drug design.
• Drug mechanisms can be classified into 4 types:
- Drugs that work not through specific targets: antacids, general anesthesia,
osmotic diuretic
- Drugs that work by changing the transport system: calcium antagonists,
cardiac glycosides, local anesthetic
- Drugs that work by changing the enzyme system: COX Inhibitors, MAO
Inhibitors, ACE Inhibitors
- Drugs acting on receptors: Hormones, Neurotransmitters
Factors affecting the effects of a drug
 DRUG TARGET
• The effect of a drug occurs when it binds to its specific molecule. The
specific molecule is a binding site called a drug target.
• Four primary drug targets are:
a. Receptors
b. Ion channels
c. Enzymes
d. Transporter
• Most specific part that binds to the drug is a protein, except:
– antitumour and antimicrobial drugs bind directly to DNA
– Biphosponat bind calcium salts on bone matrix
1. ION CHANNELS
• Ion channels are protein molecules that span the cell membrane, and
can switch between open and closes states, allowing the controlled
entry or exit of specific ions across the cell membrane.
• Drugs may bind within the ion channel and prevent the flow of ions
or may bind elsewhere on the molecule and increase or decrease the
probability of the channel opening.
• Ex. Local anaesthetics, which block pain pathways by blocking sodium
channels and therefore preventing the action potential that carries the
pain signal from the site of injury to the brain
2. ENZYME
• Drugs can mimics the natural substrate
acting as a competitive inhibitor of the
enzyme, Ex. angiotensin converting enzyme
(ACE) inhibitor (captopril), or the binding is
non-competitive and irreversible. Ex.
Cyclooxygenase (COX) -2 inhibitor (aspirin)
• Drugs may also act as false substrates,
where the drug molecule undergoes
transformation to form an abnormal
product that subverts the normal metabolic
pathway. Ex. anticancer drug fluorouracil,
which replaces uracil as an intermediate in
purine biosynthesis, but cannot be
converted into thymidylate, thus blocking
DNA synthesis and preventing cell division.
3. TRANSPORTER/ CARRIER MOLECULES
• Transportation of polar molecules across lipid membranes often
requires a carrier protein. The carrier proteins embody a recognition
site that makes them specific for a particular permeating species, and
these sites can also be targets for drugs, whose effect is generally to
block the transporter.
• Ex. Selective Serotonin Reuptake Inhibitors (SSRIs) for depression.
4. RECEPTORS
• The macromolecular component of the cell which specifically
recognise a drug molecule and upon binding undergo a conformation
change leading to activation/ inhibition of cell signalling.
• Receptors are generally Proteins
• Molecules that can act as a receptor:
– Enzyme (class of tyrosine kinase)
– Membrane protein (Glycoprotein, Lipoprotein)
– Nucleic acid (Antibiotic receptors)
– Polysaccharide complex
 RECEPTOR CHARACTERISTICS
• has specificity "lock and key mechanism"
• produce a selective response
• has sensitivity
TYPE OF PROTEIN AT THE RECEPTOR
• Regulator: mediates the action of endogenous ligand ex.
hormone
• Enzyme: inhibits / activates
• Transport: mediates ion ex transport. Na / K ATP ase in digitalis
glycosides
• Structural: integrated in ex cell structure. tubulin (colchicine
receptor)
FOUR MAIN FAMILIES OF RECEPTOR
• Ligand Gated Ion Channels
• G-protein coupled receptors
• Kinase-linked receptors
• Nuclear Receptors
1. LIGAND GATED ION CHANNELS

• Multi-subunit complexes
• The receptor is bonded to an ion channel. The ligand binding to this
receptor causes the opening of the ion channel so that it will convert
the membrane potential into depolarization or hyperpolarization
depending on the incoming / outgoing ions.
• Usually receptor for the neurotransmitters
• Mediate fast signal transmission at synapses
• Ex. Receptors for Acethilcholine nicotinic, Glutamat, GABA
2. G-PROTEIN COUPLED RECEPTORS (GPCR)
• Single polypeptide chain threaded back and forth resulting in 7
transmembrane a helices, composed of several subunits with sub unit
α has GTPase activity (inhibitory or stimulatory).
• The most common receptor for biogenic amines, eicosanoids, fat
signaling molecule, peptide, protein ligands
• Target for GPCR:
– Adenilat siklase
– Phospolipase C
– Ion Channel (esp. Ca2+ and K+)
– Rho A kinase
– PI3K
– MAPK
2004-2005
 GPCR desensitization
• Fosforilation
the effect is not specific so it can
affect other receptors so-called
heterologous desensitization

• Internalization
The phosphorylases in GRK are
very specific and will only work
on the activated receptor so that
it is called homologous
desensitization. Phosphorylated
receptors act as binding sites of
beta arrestin (intracellular
proteins that block G protein
interactions and act as endocytic
target receptors)
3. KINASE-LINKED RECEPTORS

• This receptor has a large transmembrane protein with a large amount

of residue. The receptor controls growth and differentiation and
regulates gene transcription. There are 2 main lines of receptor
kinase:
– Race / Raf / MAPK Path which plays an important role in cell division,
growth and differentiation
– Jak / Stat pathway induced by various cytokines that play a role in the
regulation of synthesis and release of inflammatory mediators
• Types of receptor kinase can be grouped into 3:
o Tyrosine kinase receptor: epidermal growth factor, nerve growth
factor, toll-like receptor
o Serine receptor / Treonin kinase (not much): transforming growth
factor
o The cytokine receptor: has no intrinsic enzyme activity, if it is
activated it will associate and activate another tyrosine kinase
2004-2005
4. NUCLEAR RECEPTORS

• Receptors for steroid hormone, thyroid hormone, vitamin D, and

retinoids are soluble proteins that bind to DNA and regulate the
transcription of specific genes.
• These receptors are grouped into 2 groups:
– Type I: Receptors located in the cytoplasm in the form of dimer and
translocated to the nucleus. High affinity. The ligand is generally the
endocrine (steroid). Ex: Estrogen Receptor (ER), Glucocorticoid
Receptor (GR)
– Type II: Receptors are in the nucleus in the form of heterodimer. Ligand
is generally a lipid. The ligand is generally the endocrine (tyroid). Ex:
Thyroid Receptor (TR)
– Hybrid: Receptors are in the form of heterodimer with Retinoid X
receptor (RXR). Low affinity. Ex: Peroxisome Proliferator Actovator
Receptor (PPAR), Retinoid Receptor (RXR)
HOW DO DRUGS BIND TO RECEPTORS

• Drug receptor complx formation is promoted by chemical bonds

between functional groups on the drug and the receptor.
• The strength of receptor binding depends on the type of bonds
formed.
• Type of Bonds:
– Covalent bond
– Ionic bond
– Hydrogen bond
– Van der Waals bond
– Hydrophobic bond
ِ ‫اب َد َوا ُء ال هد‬
‫اء‬ َ ‫ص‬َ َ‫ ِل ُك ِل َداءٍ َد َوا ٌء فَإِ َذا أ‬: ‫َّللا‬
ِ ‫سو ُل ه‬ ُ ‫ قَا َل َر‬:‫َّللا قَا َل‬
ِ ‫ع ْب ِد ه‬
َ ‫عن َجابِ ِر ب ِْن‬
)‫َّللا (رواه مسلم‬ ‫بَ َرأَ ِبإِ ْذ ِن ه‬

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