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A continuous response
BP, HR, FBG, Cholesterol,…
GRADED DOSE RESPONSE CURVE
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% of Maximal
Effect
0
20
40
60
80
100
0 200 400 600 800
Max effect = Emax Effect when all the R are occupied by D
C that gives the half-maximal effect
E= -----------
Emax xC
C+ EC50
As C ↑ response
increment ↓
0
20
40
60
80
100
1 10 100 1000
% of Maximal
Effect
EC50
Graded dose-response curves are used to determine:
1.The max efficacy (E max) → highest limit of dose-response relationship on response axis.
2.The potency = The concentration of drug required to produce a specified response
The smaller the EC50 , the greater the potency of the agonist, the lower C needed to
elicit the maximum biological response.
3. Compare the relative potency and efficacy of drugs that produce the same effect.
EC50
[C]
[C]
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GRADED DOSE RESPONSE CURVE
A > e f f i c a c y t h a n
B
B P a r t i a l A g o n i s
t
E F F I C A C Y
POTENCY
A > potent B
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X > potent than Y & Z
X & Z > e f f i c
a c y t h a n Y
X & Z a r e e q u a l e f f i c a c y
Y> potent than Z
GRADED DOSE RESPONSE CURVE
Y > potent but
< efficacious than Z
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QANTAL DOSE RESPONSE CURVE
All-non responses
% s u b j e c t s
r e s p o n
d i n g
Dose-frequency relationship
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QANTAL DOSE RESPONSE CURVE: used to determine
at which 50% of individuals exhibit the specified therapeutic response
Therapeutic Index The relation between dose to induce a desired
effect versus that producing the unwanted effect.
TD50
ED50
When low → the drug has a narrow margin of safety digoxin
When high → the drug has a safe profile diazepam
0
20
40
60
80
100
1 10 100 1000
[Dose]
ED50
%
s u b j e c t s r e s p o n d i n g
TD50 LD50 Median toxic dose
Median lethal dose
Median EffectiveDose
Therapeutic EffectToxic Effect
Lethal Effect
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Types
Physiological
Chemical
Pharmacokinetic
Non-Competitive
It is the diminution or the complete abolishment of the effect of one drug in the presence of another.
Receptor Blockade (Competitive )
Two drugs react chemically resulting in loss of activity of activedrug
Dimercaprol reduces heavy metal toxicity [ lead, cadmium ….]
Two drugs possess opposing actions in the body, so tend to
cancel each other’s effect
The antagonist effectively reduces the concentrationof the active drug at the site of action
Phenobarbitone induces an accelerated hepatic metabolism warfarine
Nor adrenaline & histamine Omeprozole & histamine
ANTAGONISM
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Receptor
Blockade
Competitive
Non-
Competitive
Antagonist prevents binding of agonist to the
receptor at the same binding site ( = competes withit at same occupancy site )
Antagonist block at some point
the chain of events that ignite
the response of agonist
Agonist and Antagonist can be bound simultaneously
Agonist and Antagonist compete ( only one is bound)
ANTAGONISM
Irreversible
Reversible
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Reversible
Antagonist readily dissociate from binding site of
agonist to the receptor
Antagonist form stable, permanent / near permanent chemical
bond with receptor.
Inactivation lasts for duration of receptor turnover or its de-novo synthesis → explains its longevity of action
Antagonism can be overcomed by increasing
concentration of agonist = Surmountable
Naloxone vs morphine
Phenoxybenzamine & Noradrenaline
Atropine vs Ach
Irreversible
COMPETATIVE ANTAGONISM
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Parallel shift to the right, without any change in slope or maximum
No parallel shift
But both a decrease in slope and a reduced maximum are obtained.
Competitive Antagonism
Irreversible
Reversible
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Agonist
Agonist + irreversible competitiveantagonist
Agonist + non-competitiveantagonist
0
20
40
60
80
100
1 10 100 1000
% of Maximal
Effect
[C]
Antagonism cannot be overcomed by increasing concentration of agonist = NON-
SURMOUNTABLE
Agonist + reversible competitiveantagonist
Competitive vs Noncompetative Antagonism
Depression of maximal
response +/- rightward
shifts ( if some R are spare )
Antagonism can be overcomed by increasing concentration of agonist = SURMOUNTABLE
Verapamil vs noradrenaline
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By the end of this lecture you will be able to :
Classify receptors into their main superfamilies
Identify the nature & time frame of their response
Recognize their different transduction mechanism
ilos
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1.Recognition
2.Reception
3.Transduction
4.Response
A RECEPTOR
Coupler
Transduction
Direct
Its Structure:
1
2 3 4
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Location
Structure
Transduction Mechanism
Classified according to their
Time scale of Response 4 Main SUPERFAMILIES
Channel-Linked Receptor
G-Protein Coupled Receptors
Nuclear Receptors
Enzyme-Linked Receptors
Nature of Response
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Conductance Cell Signal Transcription& Translation
Cell Signal
Hours /Days
Minutes / Hours
1 2 3 4
Channel-Linked G-Protein Coupled Enzyme-Linked Nuclear
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Channel-Linked Receptor1
Ionotropic Receptor
Ligand-Gated-Ion Channel
Different from Voltage-Gated Ion Channel
Is activated by a change in action potential not by occupancy of a ligand
Involved in fast synaptic neurotransmission occurring
over millisecondsIt is activated directly when a ligand binds to the
receptor to open the channel that is incorporated as
part of its structure. Examples;
Nicotinic Ach receptor activated by AchGABA A receptor activated by benzodiazipines
NMDA receptor inhibited by glycine
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G-
Protein
G-Protein-Coupled Receptor
Metabotropic Receptor
PHOSPHORYLATION OF TARGET PROTEINS
Involved in less rapid transmission of mAch R, amine transmitters, Adr R, Dopa-minergic R, histamine R, 5-HT R…Neuropeptide R, prostanoid R, purine R,… Hormones; glycogen
Adenyl cyclase (AC) cAMP PKAPhospholipase C (PLC)IP3 Ca++ intacellular
Ca2+ /CaMCAMPKDAG PKC
An enzyme 2nd messenger
RESPONSE
Go-between proteins
Coupler
Agonist
2Composed of 3 subunits
[ g] + GDP
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g
ATP ATPATPATP
G-Protein
R
E
PKA
G-Protein-Coupled Receptor
Adenyle cyclase
g ATP ATPATPATP
R
E
cAMP
P
Channels
P
P Phosphorylate
Proteins
P
Not activated
Ligand binding activates it
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g
E
Phospholypase C
PIP2 DAG
Phosphatidic aInositol
↑
G-Protein-Coupled Receptor
IP3
Ca++
PKC
+CaM
Enzymes
Cytoskeletal Proteins
P
Channels
P
P
P
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RESPONSE
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mAch; m1, m2, m3, m4,
Adrenergic receptors; 1 & 2 / 1 & 25-HT1; 5-HT1A – 1D receptor
G-Protein-Coupled Receptor
Different Classes of Receptors
Different Receptors Subtypes
Ach R m Adrenergic R & Dopaminergic R D1 & D2 5-HT 5-HT1-2 / 5-HT 4-7
Different in G-Protein Classes
Are the Most Abundant Type
Divided according to their α
-subunits into Gs, Gi and Gq Gs and Gi produce, respective, stimulation and inhibition of AC
Gq is linked to activation of PLC-IP3 -Ca++ CaM & PKC
Show selectivity to receptors & effectors with which they couple
The a 1 Adrenoceptors couple to Gq to stimulate PLC.
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++
PLC GqGq
Bronchi Blood Vessel
PLC
G-Protein-Coupled Receptor
+
AC
Adrenoceptor 2 Adrenoceptor
Inhibitory Receptor Stimulatory Receptor
Adr
GsGi
↑cAMP cAMP
1 Adrenoceptor M1 Ach receptor
Stimulatory Receptor Stimulatory Receptor
↑Ca ++
Adr Ach
↑Ca ++
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1, 2 & AdrenoceptorsDiffer from each other both in ligand selectivity amongdrugs and in coupling to G proteins (Gq, Gi, and Gs,
respectively)M1 and M3 Ach receptors activate the Gq-PLC-IP3-Ca2+ pathwayM2 and M4 Ach receptors activate Gi to reduce the
activity of AC
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Enzyme-Linked Receptors3
Involved in slow action of; hormones (insulin), growth factors, cytokines, …..
Their cytosolic domain either:
Associate directly with an enzyme (guanyl cyclase)
Possess intrisic kinase activity (as tyrosine or serine/threonine kinase) thatcan phosphorylate itself & / or other proteins that they dock.
They control many cellular
functions as motility, growth,differentiation, division &morphogenesis.
This usually require manyintracellular signaling steps
that take time to process.
Tyrosine Kinase-Linked Receptors
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Phosphorylate other
proteins that it docks
Activated Receptor
autophosphorylates
Ligands cross link or
dimerize receptors
Tyrosine Kinase-Linked Receptors
Enzyme-Linked Receptors3
Phosphory
lateddockedproteins
Phosphorylates
other targets
RESPONSE
Examples
Insulin receptors
Growth factors
receptors
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Enzyme-Linked Receptors3
Guanyle cyclase-Linked Receptors
Atrial Natriueretic Peptide [ANP] RECEPTORS
They that have a single transmembrane spanning element.
These have integral intrinic guanylate cyclase activity .
Their 2nd messenger is cGMP
→ activates PKG → phosphorylate down stream
protein signaling molecules.
↑cGMP
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Nuclear Receptors4Are intra-cellularly located whether in cytosol or the nucleus.
Their ligands are usually either:
Extracellular lipophylic hormones; steroids, thyroids, …etc Intracellular 2nd messenger developed along signalingcascade of cell membrane receptors.
They possess a conserved areathat recognizes specific DNA
sequence in the nucleus→ once bound to their ligandsthey react as
TRANSCRIPTION FACTORSexpressing or repressing
target genes.
By this they are involved in
regulation of PROTEIN SYNTHESIS
→so are the most slowest in action.
Protein
Transcription
Translation
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Nuclear Receptors4
The activated GR complex
Up-regulates expression of anti-inflammatory proteins
Represses expression of pro-inflammatory
proteins in cytosol ( preventing the translocation
of other transcription factors from the cytosol
into the nucleus).
GLUCOCORTICOIDRECEPTOR
proteins
In Cytosol
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THYROID HORMONE
RECEPTOR
Nuclear Receptors4
Intra nuclear
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Quiz?
• An example of an agent thatexerts much of its effectsthrough intracellular receptors
that in complex form binds toDNA response elements:
• A) acetylcholineB) dopamineC) corticosteroidsD) diltiazemE) atropine
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Quiz?
• Example(s) of endogenousligands that interact withmembrane-integrated ionchannels and affect(s) ionconductance.
• A) acetylcholineB) GABAC) glutamateD) aspartate
E) glycine
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Quiz?
• Example(s) of anintracellular receptor:
–
? beta-adrenergic receptor – ? muscarinic cholinergic
receptor
– ? steroid receptor
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Quiz?
• Example(s) of agents thataffect ion conductance --affecting cellular membranepotentials
– ? acetylcholine
– ? gamma-aminobutyric
acid (GABA)
– ? aspartate
– ? glutamate
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Quiz?
• Regulatory moleculesinfluenced by G proteinsystems:
– ? adenylyl cyclase
– ? phospholipase A2,C,D
– ? calcium, potassium,
sodium ion channels
– ? transport proteins
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Quiz?
• Longer-lastingphysiological responseto drug:
• A) increase in heart ratefollowing epinephrineinfusionB) changes in geneproduct productionfollowing corticosteroid
injection.
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Quiz?
• Signal transductioninvolves G proteincoupled receptorsystems:
• A) biogenic aminesB) peptide hormonesC) steroid hormones
• D) insulin
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Quiz?
• Growth factors and insulinexert their signalling effectvia:-
A. Calcium channels
B. G-protein
C. Tyrosine kinase
D. DNA transcription