Download Spare Receptors

Refresh Your Memory! 
For which of the following drugs will
excretion be most significantly
accelerated by acidification of the urine?
(a) Weak acid with pKa of 5.5
(b) Weak base with pKa of 3.5
(c) Weak acid with pKa of 7.5
(d) Weak base with pKa of 6.5
DRUG RECEPTORS &
PHARMACODYNAMICS
Pharmacology-1
Sping semester 2017
Prof.Mayyada Wazaify
• Receptor is the component of a cell or
organism that interacts with a drug and
initiates the chain of biochemical events
leading to the drug’s observed effects.
• Drug-receptor interactions are studied
by pharmacodynamics
How receptors allow the understanding
of drug actions and clinical uses?
1. Receptors largely determine the
quantitative relations between dose or
concentration of drug and
pharmacologic effects
2. Receptors are responsible for
selectivity of drug action
3. Receptors mediate the actions of
pharmacologic agonists & antagonists
Macromolecular Nature of
Drug Receptors:
1. Regulatory proteins – mediate the actions of
endogenous chemical signals e.g. neurotransmitters,
autacoids, and hormones, as well as many drugs
2. Enzymes – most commonly may be inhibited (e.g.,
dihydrofolate reductase by methotrexate)
3. Transport proteins (e.g., Na /K
+
+
ATPase
inhibited by digitalis)
4. Structural proteins (eg, tubulin, the receptor for
colchicine, an anti-inflammatory agent)
Relation Between Drug
Concentration & Response
In vivo: complex
In vitro: simple
Concentration-Effect Curves &
Receptor Binding of Agonists:
In vitro, the relation between drug
concentration and effect is described by a
hyperbolic curve
In idealized
E max x C
or in vitro
systems
E = ----------------C + EC50
Where E is the effect observed at concentration
C; E max is the maximal response that can be
produced by the drug, and EC50 is the
concentration of drug that produces 50% of
maximal effect
Concentration-Effect Curves & Receptor
Binding of Agonists (continued):
= bound
Bmax x C
B = --------------C + KD
The equation describes the relation between drug
bound to receptors (B) and the conc. of free drug.
Bmax indicates the total conc. of receptor sites (sites
bound to the drug at infinitely high conc. of free
drug). KD (the equillibrium dissociation constant) is
the conc. of free drug at which half-max. binding is
observed (reflects the drug affinity)
In a reciprocal fashion
Graded dose-response curve
Graded dose-drug binding
efficacy
potency
affinity
Work-out your brain! 
a.
b.
c.
d.
e.
A 55-ye old woman with CHF is to be treated
with a diuretic drug. Drugs X and Y have the
same mechanism of diuretic action. Drug X in a
dose of 5 mg produces the same magnitude of
diuresis as 500 mg of drug Y. This suggests that:
Drug Y is less efficacious than drug X
Drug X is about 100 times more potent than drug Y
Toxicity of drug X is less than that of drug Y
Drug X is a safer drug than drug Y
Drug X will have a shorter duration of action than drug
Y because less of drug X is present for a given effect
Competitive and irreversible antagonists
Competitive Antagonists
In the presence of a fixed concentration of
agonist, increasing concentrations of a
competitive antagonist progressively
inhibit the agonist response; high antagonist
concentrations prevent response completely;
Conversely, sufficiently high concentrations of
agonist can completely surmount the effect of
a given concentration of the antagonist, ie
Emax for the agonist remains the same for any
fixed conc. of antagonist
Competitive Antagonists
Schild equation:
C’
[I]
----- = 1 + ----C
KI
Where C’ is the conc. of agonist required to
produce a given effect in the presence of a
fixed conc. ([I]) of competitive antagonist, C
is the agonist concentration required to
produce the same effect in the absence of
the antagonist; KI is the dissociation constant
Irreversible Antagonists
The antagonist’s affinity for the receptor is so
high that the receptor is unavailable for
binding of agonist
The number of remaining unoccupied
receptors may be too low for the agonist to
elicit maximal response
If spare receptors are present, however, a
lower dose of irreversible antagonist may
leave enough receptors unoccupied to allow
achievement of maximum response to agonist
(with higher agonist conc.)
Concentration-Effect Curves &
Receptor Binding of Agonists
(continued):
Plotting the drug effect against the
logarithm of the dose or concentration
transforms the hyperbolic dose-response
curve into a sigmoid curve with linear
midportion.
This expands scale at low concentrations
(where the effect is changing rapidly) and
compresses it at high concentration (where
the effect is changing slowly)
Receptor-Effector Coupling
Binding of agonist to the receptor is the
first step of pharmacologic response
The transduction process between
occupancy of receptors and drug
response is often termed coupling
Occupancy-response coupling
efficiency is determined by:
- Initial conformational change in the
receptor (full agonist versus partial
agonist)
- Biochemical events that transduce
receptor occupancy into cellular
response
- “spare” receptors
Spare Receptors
Receptors are said to be “spare” for a given
pharmacologic response when the maximal
response can be elicited by an agonist at a
concentration that does not result in
occupancy of the full complement of available
receptors
Spare receptors are not qualitatively different
from nonspare receptors
They are not hidden or unavailable, and when
occupied, they can be coupled to response
Spare Receptors (continued)
In practice, to determine the presence of
spare receptors, we compare EC50 and Kd. If
EC50 is less than Kd, spare receptors are said
to exist;
This indicates that to achieve 50% of the
maximal effect, fewer than 50% of receptors
must be activated
How could this phenomenon be
explained?
Spare Receptors
Mechanisms:
1. The effect of the drug-receptors interaction
may persist for a much longer time than the
interaction itself
eg, binding of GTP by an intermediate may greatly outlast
the agonist-receptor interaction (the “spareness” is
temporal)
2. The actual number of receptors may exceed
the number of effector molecules available
Important Note:
The presence of spare receptors
increases sensitivity to the agonist
because the likelihood of a drug-receptor
interaction increases in proportion to the
number of receptors available;
Spare Receptors (continued)
The sensitivity (EC50) of a cell or tissue to a
particular conc. of agonist may depend not
only on the affinity of the receptor for
binding an agonist (KD) but also on the degree
of spareness, i.e. the total number of receptors
compared to the number actually needed to
elicit a maximal biologic response
The KD of the agonist-receptor interaction
determines what fraction (B/Bmax) of total
receptors will be occupied at a given free conc.
(C) of agonist regardless of receptor conc.
Spare Receptors (cont’d)
B
----Bmax
C
= -------C + KD
If we have a cell with four receptors and four
effectors, the number of effectors does not
limit the maximal response, and the receptors
are not spare in number
Partial Agonists
Partial agonist produces a lower response
at full receptor occupancy than do full
agonists.
Partial agonists produce concentration-effect
curves that resemble those observed with full
agonists in the presence of irreversible
antagonist
The failure to produce a “full” maximal
response is not due to decreased affinity for
binding to receptors
How can an agonist be
“partial”?
The precise mechanism is not known.
We can imagine that a receptor can take two
shapes: the inactive form, and an active
form, in the absence, as well as the presence
of bound ligand;
A full agonist binds to the active form more
tightly than to inactive form; while a partial
agonist has an affinity for both active and an
inactive forms. As a result, some receptors
will remain in inactive form, so that promote
less pharmacologic effect
N.B.
A partial agonist is less efficacious than the
full agonist but it could be more, less or of
equal potency to the full agonist…
How come?
Important: Figure 2-4, pp.17 (Katzung,
2004)
A problem?
Ask Me! 
Mechanisms of drug
antagonism other than at the
same receptor
1) Chemical antagonism - one drug binds
and inactivates another drug (need not
involve a receptor) (eg, protamine sulfate,
(+) protein, is an antidote for heparin (-)
charged
2) Physiologic antagonism -using opposing
regulatory pathways (eg, insulin opposes
hyperglycemic effect of glucocorticoids
through different receptors).
Wake Up!
Q: Which of the following statements about
spare receptors is MOST correct?
a.
b.
c.
d.
e.
Spare receptors, in absence of a drug, are sequestered in the
cytoplasm
Spare receptors will be detected if the intracellular effect of
drug-receptor interaction lasts longer than the drug receptor
interaction itself
Spare receptors influence the maximal efficacy of the drugreceptor system
Spare receptors activate the effector machinery of the cell
without the need for a drug
Spare receptors maybe detected by the finding that the EC50
is greater than Kd for the agonist
Important notes before you go!
Intrinsic activity: the maximum response
to an agonist (Emax)
Intrinsic activity of a full agonist is always =1
We compare potency of drugs by measuring
their EC50 values
Partial agonists cannot have spare receptors
because they do not produce a maximum
response even at full occupancy of a receptor
SIGNALING
MECHANISMS & DRUG
ACTION
Signaling
Signaling= carrying chemical
information across the plasma membrane
Five Known Transmembrane Signaling Mechanisms
Five basic mechanisms of
transmembrane signaling
1) a lipid-soluble ligand crosses
membrane and acts on an intracellular
receptor
2) a transmembrane receptor located on
membrane-spanning enzymes
3) A transmembrane receptor that binds
and stimulates a protein tyrosine
kinase
Five basic mechanisms of
transmembrane signaling
4) a ligand-gated transmembrane ion
channel that can be induced to open or
close by binding of a ligand
5) a transmembrane receptor protein that
stimulates a GTP-binding signal
transducer protein (G protein), which in
turn generates an intracellular second
messenger