Basic concepts of pharmacology Along with pharmacodynamic parameter and types of drug action Types of receptors and mechanism

24.  NT binds to receptor
 NT = key
 Receptor = lock

25. Receptor A
NT

26. Receptor B
Receptor A
NT

27. Receptor B
Receptor A
NT

28. Receptor B
Receptor A
NT
Specificity of drugs
Drug A
Drug B

30. 3 Enzyme-linked receptors
a transmembrane receptor that binds and
stimulates a protein tyrosine kinase.
4 Intracellular receptors
a lipid-soluble ligand that crosses the
membrane and acts on an intracellular receptor

31. 1. enzyme linked
(multiple actions)
2. ion channel linked
(speedy)
3. G protein linked
(amplifier)
4. nuclear (gene) linked
(long lasting)

33. Ligand
gated
G-protein
coupled
Enzymatic Nuclear
Location Membrane Membrane Membrane Intracellular
Effector Ion channel Ion Channel
or enzyme
Enzyme Gene
Coupling Direct G-protein Direct Via DNA
Example Cholinergic
Nicotinic
Cholinergic
Muscarinic,
Adrenocept
ors
Insulin
receptors
Steroid,
hormone
receptors

34. • The first receptor family comprise ligand-
gated ion channels that are responsible for
regulation of the flow of ions across cell
membranes.
• The activity of these channels is regulated by
the binding of a ligand to the channel.
• Response to these receptors is very rapid,
enduring for only a few milliseconds.
• These receptors mediate diverse functions,
including neurotransmission, cardiac conduction,
and muscle contraction.

35. • For example, stimulation of the nicotinic receptor
by acetylcholine results in sodium influx,
generation of an action potential, and activation of
contraction in skeletal muscle.
• Benzodiazepines, on the other hand, enhance the
stimulation of the γ-aminobutyric acid (GABA)
receptor by GABA, resulting in increased chloride
influx and hyperpolarization of the respective cell.
• Although not ligand-gated, ion channels, such as
the voltage gated sodium channel, are important
drug receptors for several drug classes, including
local anesthetics

38. G protein-coupled receptors (GPCRs), also known
as seven-transmembrane domain receptors, 7TM
receptors, serpentine receptor, and G protein-
linked receptors (GPLR), constitute a
large protein family of receptors that sense
molecules outside the cell and activate inside signal
transduction pathways and ultimately, cellular
responses.
They are called seven-transmembrane receptors
because they pass through the cell membrane seven
times.

39. The ligands that bind and activate these
receptors include:
Light sensitive compounds
Hormones and
Neurotransmitters (nor epinephrine,
dopamine, serotonin, acetylcholine)
That vary in size from small molecules
to peptides to large proteins.

41. Rhodopsin Receptor Family
Family of proteins comprise of G protein-coupled
receptors and transduces signals from light as they
are extremely sensitive to light. It activates the G
protein transducin (Gt) to activate the visual photo
transduction pathway.
Mutation of the rhodopsin gene is a major
contributor to various retinopathies.

45. G protein complexes are
Made up of alpha (α), beta (β)
and gamma (γ) subunits.
Beta and gamma subunits
can form a stable dimeric
complex referred to as the
beta-gamma complex.

49. G Protein Receptors Signaling Pathway
GS Beta adrenergic
receptors, glucagon,
histamine(H2),
serotonin,
activate Adenylyl
cyclase, increase
CAMP
Excitatory effects
Gi Alpha2 adrenergic
receptors, mAch R
(M2), opioid,
serotonin
inhibit Adenylyl
cyclase, decrease
CAMP
Cardiac K+ channel
open- decrease heart
rate
Gq mAch R (M1, M3),
serotonin 5HT1C, alpha
1, histamine(H2).
Increase Cytoplasmic
Ca
Gt Rhodopsin and colour
opsins in retinal rod
and cone cells
Increase cGMP

50. Receptor
trans-
ducer
primary
effector
external signal: nt
2d messenger
secondary effector
Receptor
trans-
ducer
primary
effector
external signal: nt
2d messenger
secondary effector
GS
norepinephrine
cAMP
protein kinase A
b adrenergic -R
adenylyl
cyclase

51. Second Messengers
Second messenger” molecules (also called effector
molecules) are part of the cascade of events that
translates ligand binding into a cellular response.
•Small, non protein, water-soluble molecules
or ions, readily spread throughout the cell by
diffusion
•A common pathway turned on by Gs, and
other types of G proteins, is the activation of
adenylyl cyclase by α-GTP subunits,

52. which results in the production of cyclic
adenosine monophosphate (cAMP)—a second
messenger that regulates protein phosphorylation.
Increases in (cAMP) causes many possible responses:
• mobilization of stored energy( breakdown of CHO
in liver or triglycerides in fat cells)
• Conservation of water by kidney
• Calcium homeostasis
• Increase rate and force of contraction of heart
• Relaxation of smooth muscles
• Endocrine and neural processes

53. • G proteins also activate phospholipase C,
which is responsible for the generation of
two other second messengers, namely
inositol-1,4,5-trisphosphate (IP3) and
diacylglycerol (DAG). IP3 is responsible for
the regulation of intracellular free calcium
concentrations, and of other proteins as
well.

54. • Calcium more widely used than cAMP e.g. used
by neurotransmitters, growth factors, some
hormones
• Increases in Ca2+ causes many possible
responses:
•Muscle cell contraction
•Secretion of certain substance
•Cell division
• DAG activates several enzymes such as protein
kinase C (PKC) within the cell leading to a myriad
of physiological effects.

60. • Binding of a ligand to an extracellular domain
activates or inhibits this cytosolic enzyme activity.
• Duration of responses to stimulation of these
receptors is on the order of minutes to hours.
Metabolism, growth, and differentiation are
important biological functions controlled by these
types of receptors.

62. • Typically, upon binding of the ligand to receptor
subunits, the receptor undergoes
conformational changes, converting kinases from
their inactive forms to active forms.
• The activated receptor autophosphorylates and
then phosphorylates tyrosine residues on specifi
c proteins. The addition of a phosphate group
can substantially modify the three-dimensional
structure of the target protein.

63. • For example, when the peptide hormone insulin
binds to two of its receptor subunits, their
intrinsic tyrosine kinase activity causes auto
phosphorylation of the receptor itself.
• In turn, the phosphorylated receptor
phosphorylates target molecules (insulin-receptor
substrate peptides) that subsequently activate
other important cellular signals, such as inositol
triphosphate and the mitogen-activated protein
(MAP) kinase system.
• This cascade of activations results in a
multiplication of the initial signal.

67. • The ligand must have sufficient lipid solubility.
• The primary targets of these ligand-receptor
complexes are transcription factors.
• The activation or inactivation of these factors causes
the transcription of DNA into RNA and translation of
RNA into an array of proteins.
• For example, steroid hormones exert their action on
target cells via this receptor mechanism. The activated
ligand–receptor complex migrates or translocates to
the nucleus, where it binds to specific DNA sequences,
resulting in the regulation of gene expression

68. • Other targets of intracellular ligands are
structural proteins, enzymes, RNA, and
ribosomes.
• For example, tubulin is the target of
antineoplastic agents such as paclitaxeL, the
enzyme dihydrofolate reductase is the target of
antimicrobials such as trimethoprim, and the 50s
subunit of the bacterial ribosome is the target
of macrolide antibiotics such as erythromycin.

72. .
For example
• Spare receptors are exhibited by insulin
receptors, where it has been estimated that 99
percent of the receptors are “spare.”
• This constitutes an immense functional reserve
that ensures that adequate amounts of glucose
enter the cell.
Spare Receptors
Term used to describe the situation in which
maximum tissue response occurs when not all the
receptors of the tissue are occupied by the drug