Pharmacodynamics

By
Hanan S. M. Farghaly, Ph.D.
 Lecture 4
Drug Receptors, Signaling Mechanisms and
Drug Action
Intended Learning Outcomes (ILOs)
 List types of drug-receptor interactions
 Identify receptor-effector coupling & spare
receptors
 Describe signaling mechanisms & drug action
1. Which of the following is NOT a second messenger
associated with G proteins?
a) DAG b) GDP c) IP3
d) cAMP e) cGMP
2. Muscarinic ACh receptors and adrenergic receptors are
associated with which of the following type of receptors?
a) Intracellular receptors for lipid soluble ligands
b)Transmembrane receptors with enzymatic cytosolic domains
c) G-protein coupled receptors
d) Ligand-gated ion channels
3. All of the following receptors match with their time scale
except:
a) Insulin receptor-----------------------Minutes
b) Muscarinic ACh receptor-----------Seconds
c) Estrogen receptor--------------------Hours
d) Nicotinic ACh receptor--------------Days
 MECHANISMS OF DRUG ACTION

1-Binding to specific receptors:

 located on the cell membrane: Histamine, Adrenergic,
Cholinergic receptors
 Located inside the cell: eg., steroid receptors

2-Direct interaction with voltage-gated ion channels: that

transport ions across the plasma membrane.
 Local anesthetics block voltage-sensitive Na+ channels in
sensory neurons
 Ca++ Channel blockers block voltage-gated L-type Ca++
channels in vascular smooth muscle & the heart
 Oral antidiabetics (Sulphonylureas) block ATP-sensitive K+
channels in the insulin secreting β-cells
3- Enzymes : Reversible or Irreversible modification of
the enzyme
E.g., Sulphonamides compete with PABA for the enzyme
dihydropteroate synthase, Aspirin inhibits cyclooxygenase,
Organophosphorous compounds inhibit cholinesterase enzyme

4- Direct chemical interaction:

Antacids with gastric acid.

5- Physical or Physicochemical interaction:

 The purgative MgSO4 & Mannitol (due to osmotic effects)
6- Some drugs are structural analogs to a normal cell
constituent thus, incorporate into cellular components & alter
their function: eg., 5-flurouracil

DRUG-RECEPTORS
Receptor = cellular macromolecule to which the drug binds
to initiate its effects. The Receptor has 2 functions:
Ligand (molecules that attach selectively to a particular
active site) binding - Affinity.
 Message propagation of the regulatory signal in the target
cell- intrinsic activity. Related to its maximal effect
 Best fit -- highest
affinity

Some fit; no
cellular effect;
block receptor
preventing its
activation by drug
or neurochemical
or hormone

The ability of a drug to activate a receptor and generate a cellular response is its
efficacy
 Agonists and Antagonists

 AGONIST - Has affinity for receptor and efficacy.

 ANTAGONIST - Has affinity but no efficacy.

 Competitive Antagonist
 Noncompetitive Antagonist

 Partial Agonist
Has affinity but lower efficacy than full agonist.
Type of receptors

 Ligand gated ion channels

 G protein coupled receptors

 Tyrosine Kinase linked receptors

 Intracellular receptors
 Signal transduction

A. ion channel linked B. G protein linked C. enzyme linked D. nuclear (gene) linked
(speedy) (amplifier) (multiple actions) (long lasting)
Ligand gated ion channel (iontropic
receptors)
 -amino butyric acid (GABA)
 Glycine
 Aspartate
 Glutamate
 Acethylcholine at nicotinic receptors
 5HT3
Ligand gated ion channel (iontropic receptors)
ions

Hyper polarization
or
depolarization

Cellular effects
Ionotropic receptors (ligand-gated ion channel
receptors):
They are linked directly to ion channels in plasma
membrane so that when a drug (ligand) binds to these
receptors it leads to opening of the ion channels and
ionic transport.
Example is nicotinic cholinergic receptors. When
acetylcholine neurotransmitter (as a ligand) binds to
them, it makes conformational changes in the receptor
leading to opening of sodium ion channels and sodium
transport into the cell. Therefore, these receptors are
termed "ligand-gated ion channel receptors". They are
usually involved in fast synaptic transmission.
Other receptors of this group are GABA receptors,
5HT3 receptors and glutamate receptors.
G protein coupled receptors
 Catecholamines
 Acetylcholine at muscarinic receptors
 Angiotensin
 Histamine
 Seretonin except 5HT3
 Vasopressin
 Ions G protein coupled receptors

R E
G G
+ - + -

Change in Second messengers

excitability

Ca2+ release Protein other

phosphorylation

Cell effects
 Binding of a drug to the receptor triggers the
activation of a G-protein which regulates the activity
of effectors (e.g. adenylcyclase, phospholipase
enzymes or open related channel) leading to change
in the concentration of an intracellular second
messenger such as cAMP, cGMP, inositol
triphosphate (IP3), diacylglycerol (DAG) or Ca++.
Well Established Second Messengers
 Cyclic Adenosine Monophosphate (cAMP)
 Cyclic Guanosine Monophosphate (cGMP)
 Calcium
 Phosphoinositides e.g. inositol-1,4,5-
trisphosphate (IP3) and diacylglycerol (DAG)
Well Established Second Messengers

 Cyclic Adenosine Monophosphate (cAMP)

 Calcium and Phosphoinositides
 Cyclic Guanosine Monophosphate (cGMP)
Tyrosine Kinase linked receptors as insulin

R/E

Protein
phosphorylation

Protein synthesis

Cellular effects
These are transmembrane receptors that have two
domains: an extracellular domain for drug binding and
a cytoplasmic domain with enzymatic activity e.g.
tyrosine kinase enzyme.
Binding of the drug to the extracellular domain
stimulates the enzyme tyrosine kinase leading to
phosphorylation of target proteins t tyrosine residue to
produce the desired effect. The intracellular signal
produced by ligand binding may continue even after
the ligand has been dissociated from the binding site
"hit and run mechanism of action".
Example of this mechanism is insulin receptors
 Intracellular receptors

Nucleus
R

R Gene
R transcription

Protein synthesis

Cellular effects
These receptors are not associated with plasma membrane
and are located intracellular.
The ligands related to these receptors are lipid soluble and can
cross the cell membrane e.g. steroid hormones, thyroid
hormone and vitamin D.
There is a protein called heat shock protein-90 (HSP-90) which
is usually attached to the receptor in the absence of agonist.
When the receptors are stimulated by these ligands, HSP-90
dissociates from the receptors. The receptors then translocate
to the nucleus and bind to a DNA response element which
consequently initiates an expression of target genes.
These activated genes in turn lead to change in the levels of
proteins synthesized by target tissues.
This kind of signaling reaction is relatively slow and requires
from 30 minutes up to several hours. Also, the duration of
response can last long after the concentration of ligand has
fallen to zero.
Spare Receptors:
 Spare receptors are said to exist if the
maximal drug response is obtained at less
than maximal occupation of the receptors.
 Receptors which amplify signal duration and
intensity are said to have spare receptors
 For example, the maximal inotropic response
of heart muscle to catecholamines can be
elicited even when 90% of β adrenoceptors to
which they bind are occupied by an
irreversible antagonist.
Drug actions: initial consequences of drug/living
system interaction at cellular and subcellular level
Drug effects: Events that follow drug actions

Thanks
1. Which of the following is NOT a second messenger
associated with G proteins?
a) DAG b) GDP c) IP3
d) cAMP e) cGMP
Answer b) GDP
2. Muscarinic ACh receptors and adrenergic receptors are
associated with which of the following?
a) Intracellular receptors for lipid soluble ligands
b)Transmembrane receptors with enzymatic cytosolic domains
c) G-protein coupled receptors
d) Ligand-gated ion channels
Answer c) G-protein coupled receptors
3. All of the following receptors match with their time scale
except:
a) Insulin receptor-----------------------Minutes
b) Muscarinic ACh receptor-----------Seconds
c) Estrogen receptor--------------------Hours
d) Nicotinic ACh receptor--------------Days
Answer d) Nicotinic ACh receptor--------------Days
Good Luck