Pharmacodynamics

Targets of
Drug Action
Dr. Aung Kyaw Moe

Learning Outcomes:
The student should be able to:
understand the concept of pharmacodynamics and
drug-body interactions
list the 4 major protein targets of drug action:
receptors, ion channels, enzymes, carrier molecules.
describe the various types of receptors and ion
channels that serve as drug targets.

Pharmacology
Mechanism of action
Actions / Pharmacological effects
Pharmacokinetics

Indications / Therapeutic uses / Clinical uses

Unwanted/untoward/side/adverse effects/toxicity
Cautions/warnings
Contraindications/should be avoided in

Benefits/advantages
Risks/disadvantages
Preparations
Dosage regimen (dose size/dosing interval/duration of treatment)
Drug interactions

How
drugs
act ?

Central
compartment
(Blood)

Peripheral
compartment
(Target tissue)

Peripheral compartment: Tissue/ cells major site of drug action

Drug target: cell surface proteins/ intracellular proteins

Drug + target protein cellular reactions response (s)

TARGETS FOR DRUG ACTION

A drug is a chemical applied to a physiological system
that affects its function in a specific way.
With few exceptions, drugs act on target proteins,
namely:
receptors
enzymes
carriers
ion channels.
Biological
Response

MECHANISM OF DRUG ACTION

Majority of drugs produce their effects by interacting with a

discrete target biomolecule, which usually is a protein. Such

mechanism confers selectivity of action to the drug.
Functional proteins that are targets of drug action can be
grouped into four major categories, viz. enzymes, ion channels,
transporters and receptors.
However, a few drugs do act on other proteins (e.g.
colchicine, vinca alkaloids, taxanes bind to the structural
protein tubulin) or on nucleic acids (alkylating agents).

Assembly

Disassembly

(Polymerization)

(Depolymerization)

MECHANISM OF DRUG ACTION

Only a handful of drugs act by virtue of their simple physical

or chemical property; examples are:

Bulk laxativesphysical mass
Activated charcoaladsorptive property
Mannitol, Magnesium sulfateosmotic activity
131I

and other radioisotopesradioactivity

Antacidsneutralization of gastric HCl
Chelating agents (EDTA, dimercaprol)chelation of heavy
metals.

Four major types of biomacromolecular targets of drug action.

(A) Enzyme; (B) Transmembrane ion channel; (C) Membrane bound transporter; (D) Receptor

Protein targets for drug action

Protein targets for drug action

Receptors
Receptor: protein molecule located on
the surface or inside of cells
Function: sensing elements to
recognize the ligand and initiate the
biologic response
Drugs can act as agonist or antagonist
on the receptors

Ion channels

Membrane proteins
Function: to regulate the flow of ions across the biological membrane
Main type of ion channels:
1. Ligand- gated ion channels
- ion channels change status in response to the binding of a ligand to a
receptor site incorporated into the channel structure
2. Voltage-gated ion channels
- ion channel opens or closes in response to a change in the
transmembrane electrochemical gradient

 Nai+
Cai++

Ke+
Cli-

Enzymes

Protein that catalyzes various cellular processes/ reactions

Drugs targeted on enzyme
- acts as inhibitor
- acts as false substrate
the drug molecule undergoes enzymatic transformation to form an abnormal product
that distort the normal metabolic pathway
e.g. anticancer drug fluorouracil
which replaces uracil as an intermediate in purine biosynthesis but cannot be converted
into thymidylate block DNA synthesis & prevent cell division
- acts as pro-drug
enzyme converts pro-drug from an inactive to an active form

21

Transporters
Also known as carrier molecules
Transport ions and polar
molecules across cell membrane
The carrier protein contain a
recognition site that makes them
specific for a particular
permeating polar molecules

Types of Receptor Protein

Based on molecular structure and nature of the linkage (transduction mechanism),
receptor can be sub-classified into 4 types

Type 1: Ligand-gated ion channel

Ion channels that have a receptor site incorporated to it, usually

at the extracellular domain
Involve in the regulation of ions across the membrane
Channel open/ close within a few miliseconds
e.g.: nicotinic acetylcholine receptor
- Agonist act on the receptor channel open Na+ influx

Type 2: G protein-coupled receptors (GPCRs)

Involved in cell signaling pathway

Activates intracellular effector systems via the help of G-protein
Stimulation of these receptors results in responses that last several
seconds to minutes.
Signal flow:
Ligand receptor G protein 2nd messenger system effector
systems response

The recognition of chemical signals by G proteincoupled membrane receptors

affects the activity of adenylyl cyclase. PPi = inorganic pyrophosphate.

Type 3: Kinase-linked receptors

Important in cell metabolism, growth &
differentiation
Comprise an extracellular ligand-binding
domain linked to an intracellular
enzymatic domain
Ligand binding results in receptor
dimerization (cross-linking), kinase
domain phosphorylate each other
(autophosphorylation) & become
activated phosphorylate other
protein cellular response
Time scale: hours

Type 4: Intracellular receptors

Receptors that regulate gene
transcription (e.g. Steroid
hormone, oestrogen receptors)
Many are found within the
nucleus activated by ligand
that enters the nucleus
Some are found in the cytosol
ligand- receptor complex enters
nucleus affect gene
transcription
Very slow response (hours to
days)

Mechanism of intracellular receptors

Type 1

Type 2

Type 3

Type 4

Location

Membrane

Membrane

Membrane

Intracellular

Effector

Ion channel

Channel or
enzyme

Protein
kinases

Gene
transcription

Coupling Direct

G-protein

Direct

Via DNA

Time
Scale

Seconds

Hours

Hours

Milliseconds

Nicotinic
acetylcholine
Examples receptor,
GABAA
receptor

Insulin,
Muscarinic
Growth
acetylcholine
factors,
receptor,
Cytokine
Adrenoceptor
receptors

Steroid
receptors