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Sinal - Pharmacol I 1
Drug-Receptor Interactions
Dr. Christopher Sinal
Room 5E, Tupper Medical Building
Overview:
Receptor proteins
Quantitation of Drug-Receptor Interactions
Agonists and Antagonists
Spare Receptors
Drug Desensitization
Therapeutic Index
Drug Toxicity
Reference:
Basic and Clinical Pharmacology, B. Katzung 10th Ed., Chapter 2
http://pharmacology.medicine.dal.ca/undergraduate/courses.cfm
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Sinal - Pharmacol I 2
Pharmacodynamics
D + R " DRD: Drug or endogenous ligand
R: Receptor
DR: Drug-Receptor Complex
The study of the relationship of drug concentration to drug effects.
Biological Effect [DR]
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Sinal - Pharmacol I 3
What is a Receptor?
The beneficial therapeutic effects and unwanted toxic effects of drugs are elicitedthrough interactions with proteins
-Enzymes (aspirin + cyclooxygenase)
-Transporters/Carriers (Prozac + serotonin reuptake transporter)
-Ion Channels (local anesthetics + Na+ channels)
-Receptor Proteins (cimetidine + histamine receptor)
The term receptor specifically refers to proteins that participate in intracellularcommunication via chemical signals
Upon recognition of an appropriate chemical signaling molecule (ligand), receptorproteins transmit the signal into a biochemical change in the target cell
Ligands include drugs as well as endogenous signaling molecules such ashormones and neurotransmitters
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Sinal - Pharmacol I 4
Characteristics of Specific Ligand/Receptor Interactions
-none
-compounds exist that have
opposite physiological actions
(e.g. caffeine)
-various
-treatment of allergies, gastric
ulcers
Antagonists
(blockers)
-similar pharmacological actions
over a wide range of chemically
related compounds
-small modifications have major
effects on pharmacological activity
Chemical Specificity
-various stimulatory and
depressive effects on most cells
and tissues
-contraction of bronchial smooth
muscle
-relaxation of vascular smooth
muscle
-stimulation of gastric secretion
Biological Specificity
10-2 - 10-1 M10-5 - 10-8 MEffective Concentration
AlcoholsHistamine
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Sinal - Pharmacol I 5
Major Classes of Receptors
Ligand-Gated Ion Channels
Tyrosine Kinase-Linked Receptors
G-Protein Coupled Receptors
Ligand-Activated Transcription Factors
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Sinal - Pharmacol I 6
Ligand-gated
ion channels
ions
Change in
membrane potential
or
ionic concentration
Cellular
effect
nicotinic acetylcholine
receptor
(milliseconds)
Tyrosine kinase-
linked receptors
Protein
phosphorylation
Cellular
effect
insulin
receptor
(seconds-minutes)
nucleus
mRNA
Cellular
effect
protein
estrogen receptor
(hours)
Ligand-activated
transcription factors
-adrenergic
receptor
(seconds-minutes)
Cellular
effect
Intracellular
2 messenger
(e.g. cAMP)
G-protein
coupled
receptors
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Sinal - Pharmacol I 8
Chemistry of Drug-Receptor Interactions
Most drug-receptor interactions
-reversible
-weak chemical bonds
Irreversible drug-receptor interactions-not common
-strong chemical bonds (covalent)
-e.g. aspirin, anti-tumour drugs
-usually undesirable
-reversal of effects/toxicity
-mutagenicity/carcinogenicity
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Sinal - Pharmacol I 9
Relationship of Drug Concentration and Receptor Binding
1
FractionofReceptorsBo
und(B)
5 100
Drug Concentration [D]
0.5
Hyperbolic Concentration-Binding Curve
Bmax
Kd
B =Bmax " [D]
[D] +Kd
B -Fraction of available receptors
bound
Bmax -Maximal binding of receptors
(=1)
[D] -Concentration of drug
Kd -Equilibrium Dissociation
Constant-Drug concentration at which
1/2 of available receptors are
bound
-Measure of affinity of
drug/receptor interaction
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Sinal - Pharmacol I 10
Sigmoidal Receptor Binding Curves
1
FractionofReceptorsBound(B)
5 100Drug Concentration [D]
Bmax
Kd
0.5
1010.1Drug Concentration [D]
Bmax
Kd
1
FractionofR
eceptorsBound(B)
0.5
-Semi-logarithmic transformation
-Common representation of pharmacological data
-Expands concentration scale at low concentration (where binding is changing rapidly)
-Compresses concentration scale at high concentrations (where binding is changing slowly)
-Does not change value of Bmax and Kd
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Sinal - Pharmacol I 11
Graded Dose-Response Curves
Emax -the maximum response achieved by an agonist
-also referred to as drug efficacy
ED50 -the drug concentration (or dose) at which 50% of Emax is achieved
- also referred to as drug potency
1
Dilation(mm)
50Drug Concentration [D]
Emax
ED50
0.5
10 1010.1Drug Concentration [D]
Emax
ED50
1
Dilation(mm)
0.5
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Sinal - Pharmacol I 12
Quantal Dose-Response Curves
Graded Phenomena: - infinite number of intermediate states
- vessel dilation, blood pressure change, heart rate change
Quantal Phenomena: - all-or-none
- death, pregnancy, cure, pain relief, effect of given magnitude
Quantal Dose-Response Curves
Describe population rather than
single individual responses to
drugs
based on plotting cumulative
frequency distribution of
responders against the log drugdose
Drug Dose
100
Individ
ualsresponding(%
)
1.25
50
2.5 5 10 20
% of individuals whorequire this dose to
respond
cumulative response
Emax
ED50
dose-response curve
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Sinal - Pharmacol I 13
Agonist Types: Its All Relative
Drug Concentration [D]
100
Effect(%
)
0.01
50
0.1 1.0 10 100
A
A: full agonist
maximum potency,
maximum efficacyC
C: full agonist
reduced potency,
maximum efficacy
D
D: partial agonistreduced potency,
reduced efficacy
B: partial agonist
maximum potency,reduced efficacy
B
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Sinal - Pharmacol I 14
Types of Antagonism
Chemical
-interaction of two drugs in solution such that the effect of active drug is lost
e.g. metal chelators plus toxic metals
Physiological
-interaction of two drugs with opposing physiological actions
e.g. histamine: lowers arterial pressure through vasodilation (H1receptor); epinephrine raises arterial pressure throughvasoconstriction (-adrenergic receptors)
Pharmacological
-blockage of the action of a drug-receptor interaction by another compound
e.g. cimetidine blocks interaction of histamine with H2 receptorsresulting in lower gastric acid secretion
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Sinal - Pharmacol I 15
Pharmacological Antagonists
Bind to receptors, but do not activate signal transduction mechanisms
Biological effects derive from preventing agonist (drugs, endogenous) binding andreceptor activation
Competitive Antagonists
-bind to same site on receptor as agonists
-inhibition can be overcome by increasing agonist concentration (reversible)
-primarily affect agonist potency
-clinically useful
Non-Competitive Antagonists
-bind covalently to same site as agonist (irreversible) or to a site distinct from thatof agonist (irreversible or reversible)
-inhibition cannot be overcome by increasing agonist concentration
-primarily affect efficacy
-limited clinical use
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Sinal - Pharmacol I 16
Competitive Antagonists - Effect on Dose Response Curves
100
Effect(%
)
0.01
Agonist Concentration
50
0.1 1.0 10 100
A: -agonist + no antagonist
-agonist has maximum potency,
maximum efficacy
A B
B: -agonist + competitive
antagonist
-agonist has reduced potency,
but maximum efficacy
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Sinal - Pharmacol I 17
Non-Competitive Antagonists - Effect on Dose Response Curves
Effect(%
)
100
0.01
Agonist Concentration
50
0.1 1.0 10 100
A: -agonist + no antagonist
-agonist has maximum potency,
maximum efficacy
A
BB: -agonist + non-competitive
antagonist
-agonist has maximum potency,
but reduced efficacy
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Sinal - Pharmacol I 18
Constitutive Receptor Activation
R
(inactive)
Biological
Effect
R*(active)spontaneous
DR*
(active)+agonist
agonist (e.g. drug, hormone, neurotransmitter) binding induces a conformational
change in the receptor from the inactive (R) to active (R*) state
conformational change to active state can also occur spontaneously in the absence
of agonist (random kinetic fluctuations)
agonist dramatically increases the probability of conformational change and
stabilizes the active state
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Sinal - Pharmacol I 19
Inverse Agonists Reveal Constitutive Receptor Activity
1010.1Drug Concentration [D]
100
%Bio
logicalEffect
50
0
-50
Agonist
Alone
Antagonist
Alone
Inverse Agonist
Alone
constitutive
receptor
activity
Antagonist impacts receptor activity only in
the presence of agonist
Inverse Agonist
has an independent impact upon
receptor activity produces an effect opposite to
agonist
Agonist
has an independent impact upon
receptor activity
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Sinal - Pharmacol I 20
Constitutive Receptor Activation
R
(inactive)
DR*
(active)
R*(active)
+drug
spontaneous
Biological
Effect
agonist (e.g. drug, hormone, neurotransmitter) binding induces a conformational
change in the receptor from the inactive (R) to active (R*) state
conformational change to active state can also occur spontaneously in the absence
of agonist (random kinetic fluctuations)
agonist dramatically increases the probability of conformational change and
stabilizes the active state
antagonist
inverse
agonist
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Sinal - Pharmacol I 21
A Little More Math
D R DR+k+1
k-1
Biological Effect [DR]
Rate of association = k+1[D][R]
Rate of dissociation = k-1[D-R]law of mass action
At equilibrium: k+1[D][R] = k-1[DR]
[D][R]
[DR] =
k" 1
k+ 1 = K (equilibrium constan t)
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Sinal - Pharmacol I 22
Spare Receptors
In some systems, full agonists are capable of eliciting 50% response with less than50% of the receptors bound (receptor occupancy)
Pool of available receptors exceeds the number required for a full response
Common for receptors that bind hormones and neurotransmitters
Recall:
At equilibrium:
Net effect is to increase sensitivity to ligands
if [R] is increased, the same [DR] can be achieved with a smaller [D]
a similar physiological response is achieved with a smaller [D]
[D
][R
][DR]
= K
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Sinal - Pharmacol I 23
Receptor Occupancy versusPhysiological Response
biological effectED50 = 1.0
100
ReceptorOccupancyorEffect(%)
0.01Drug Concentration [D]
50
0.1 1.0 10
receptor occupancy
Kd = 1.0
100
ReceptorOccupanc
yorEffect(%)
0.01Drug Concentration [D]
50
0.1 1.0 10
biological effect
ED50 = 0.1
receptor occupancy
Kd = 1.0
System 1 - No Spare Receptors10 total receptors in system
Kd = 1
Occupancy of 5 receptors (50% of total)elicits 50% of maximum response
ED50 = 1
System 2 - Spare Receptors
50 total receptors in system
Kd = 1Occupancy of 5 receptors (10% of total)elicits 50% of maximal response
ED50 = 0.1
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Sinal - Pharmacol I 24
Receptor Occupancy versusPhysiological Response
100
Response(%
)
50 1000Receptor Occupancy (%)
50
With spare receptors:
50% response = 10% occupancy
Biological effect is proportional to
[DR] only at low drugconcentrations
With
spare receptors
Without spare receptors:
50% response = 50% occupancy
Biological effect is proportional to
[DR] at all drug concentrations
Without
spare receptors
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Sinal - Pharmacol I 25
Drug Desensitization
effect of a drug often diminishes when givencontinuously or repeatedly
desensitization, tachyphylaxis, refractoriness,
resistance, tolerance
receptor-mediated and non-receptor-mediated
mechanisms
Receptor Mediated
- loss of receptor function
- reduction of receptor number
Non-Receptor Mediated
- reduction of receptor-coupled signaling components
- reduction of drug concentration
- physiological adaptation
100
BiologicalEffect
2 100Time (h)
50
4 6 8
Response
continuous ligand exposure
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Sinal - Pharmacol I 26
Receptor Mediated Desensitization
100
%ofControl
2 100Time (h)
50
4 6 8
ResponseReceptor #
continuous ligand exposure
1. Loss of Receptor Function
-rapid desensitization due to change in
receptor conformation
-usually due to feedback of cellular
effects of agonist-Example: phosphorylation of specific
amino acids in G-protein coupled
receptors blocks coupling to G-proteins
loss ofreceptor function
2. Reduction of Receptor Number
-slower, long-term desensitization due to change in receptor number
-usually due to feedback of cellular effects of agonist
-Example: phosphorylation of specific amino acids in G-protein
coupled receptors causes removal from cell surface
reduction ofreceptor number
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Sinal - Pharmacol I 27
Non-Receptor Mediated Desensitization
1. Reduction of Receptor-Coupled Signaling Components-depletion of signaling molecules required for biological response
-Example: prolonged stimulation of G-protein coupled receptors can lead to
depletion of intracellular secondary messengers
2. Increased Metabolic Degradation
-increase in the rate of metabolism and/or elimination of drug-lowers plasma drug concentrations
-Example: barbiturates induce the expression of metabolic enzymes (cytochrome
P450s) that degrade this drug
3. Physiological Adaptation
-reduction or amelioration of drug effects due to opposing homeostatic response
-very few well characterized mechanisms
**all of these receptor and non-receptor dependent factors can also contribute to
interindividual differences in drug response**
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Sinal - Pharmacol I 28
Beneficial versusToxic Drug Effects
Paracelsus 1493-1541
(the father of toxicology)
it is not the nature of the drug that
determines toxicity, but rather the
amount
everything, in excess, is potentially
toxic
all things are poison and not
without poison; only the dose
makes a thing not a poison
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Sinal - Pharmacol I 29
Therapeutic Index
A measure of drug safety Considers dose required for a toxic effect versus that
required for the desired beneficial effect
Beneficial Effect
ED50 = 0.1
In general, a larger T.I.
indicates a clinically safer
drug
Effect(%)
100
0.01
Drug Concentration [D]
50
0.1 1.0 10
Toxic Effect
ED50 = 1.0
Therapeutic Index (T.I.) = Toxic ED50
Beneficial ED50
Therapeutic Index (T.I.) = 1
0.1
Therapeutic Index (T.I.) = 10
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Sinal - Pharmacol I 30
Beneficial versus Toxic Drug Effects
No drug causes only a single, specific effect
Selectivity in clinical actions is limited to a specific dose range(T.I.)
1. Effects mediated by identical receptors in the
same tissue.
2. Effects mediated by identical receptors in
different tissues.
3. Effects mediated by different receptors.
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Sinal - Pharmacol I 31
Effects Mediated by Identical Receptors in the Same Tissue
-clinically, most serious toxicities occur in this manner
-pharmacological extension of therapeutic actions of drug
-reduced primarily through careful control of drug dosage and monitoring of blood
concentration
Example: Warfarin (coumadin)
-Anticoagulant administered to patients at risk for thrombosis (clot formation)
-Excessive blood concentrations can cause gastrointestinal bleeding and inmore severe cases cerebral and other internal hemorrhage
-Requires careful therapeutic drug monitoring (narrow therapeutic range)
-International Normalized Ratio (INR)
-Compares patient blood clotting time to a recognized standard value
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Sinal - Pharmacol I 32
Effects Mediated by Identical Receptors in Different Tissues
Strategies to reduce toxicity:
-administration at lowest effective dose (monitoring)
-use in combination with other drugs that achieve a similar physiological effect but
through a different mechanism (allows lower dose)
-altered route of administration (e.g inhalers for asthma)
Example: Digoxin
-digitalis glycoside
-treatment of heart failure
-increases intracellular Ca+2 of cardiomyocytes through inhibition of Na+/K+
ATPase pump in cardiomyocytes
-increases force of contraction (positive inotropic effect)
-can also lead to impaired renal function and disruption of systemicelectrolyte balance through inhibition of Na+/K+ ATPase pump
-Therapeutic plasma concentration: 0.5 -1.5 ng/mL
-Toxic: >2 ng/mL
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Sinal - Pharmacol I 33
Effects Mediated by Different Receptors
-often, receptors exist as multiple isoforms with distinct ligand selectivity, tissue expression
patterns and physiological function-drugs may exhibit affinity for multiple isoforms
Example: adrenergic receptors
- important clinical drug targets (e.g. heart failure, hypertension, asthma)
- 9 isoforms in humans (6 alphaplus 3 beta)
Relaxation
(asthma)
Increased force
and rate of
contraction
(heart failure)
Beneficial
Action
2
1
Receptor
Respiratory,
uterine and
vascular smoothmuscle
Heart
Tissue
Terbutaline
Dobutamide
Agonists
2 > >1
1 >2
Agonist
Selectivity
Increased heart
rate, chest pains
Hypotension
(low blood
pressure)
Side Effect
Strategies to reduce toxicity:
-administration at lowest effective dose
-drug combinations
-route of administration