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Pharmacology – I
PHL-313
By
Majid Ahmad Ganaie M. Pharm., Ph.D. Assistant Professor Department of Pharmacology E mail: [email protected]
Chapter 2:
PHARMACDYNAMICS
Learning objectives:
• Principles and mechanism of drug action
• Transducer mechanisms
• Dose-response relationship
• Combined drug effects
HOW DO DRUGS WORK?
• Some antagonize, block or inhibit endogenous proteins
• Some activate endogenous proteins
• A few have unconventional mechanisms of action
Most work by interacting with endogenous proteins:
WHAT DRUG DOES TO THE BODY!
It is the study of biochemical and physiological effects of drug and their mechanism of action at organ level
as well as cellular level.
PRINCIPLES OF DRUG ACTION
- Do NOT impart new functions on any system, organ or cell
- Only alter the PACE of ongoing activity
• STIMULATION
• DEPRESSION
• IRRITATION
• REPLACEMENT
• CYTOTOXIC ACTION
PRINCIPLE OF
ACTION
MODE EXAMPLE
STIMULATION Selective Enhancement of level of activity
of specialised cells
- Excessive stimulation is often followed by
depression of that function
Pilocarpine stimulates salivary
glands
Picrotoxin – CNS stimulant
convulsions coma death
DEPRESSION Selective Diminution of activity of
specialised cells
Certain drugs – stimulate one cell type and
depress others
Barbiturates depress CNS
Quinidine depresses Heart
Ach – stimulates smooth muscle
but depresses SA node
IRRITATION Non-selective often noxious effect –
applied to less specialised cells
(epithelium, connective tissue)
-stimulate associated function
Bitters – salivary and gastric
secretion
Counterirritants increase blood
flow to a site
REPLACEMENT Use of natural metabolites, hormones or
their congeners in deficiency states
Levodopa in parkinsonism
Iron in anaemia
CYTOTOXIC
ACTION
Selective cytotoxic action for invading
parasites or cancer cells – for attenuating
them without affecting the host cells
Penicillin, chloroquine
MECHANISM OF DRUG ACTION
MECHANISM OF DRUG ACTION
• MAJORITY OF DRUGS INTERACT WITH TARGET
BIOMOLECULES:
Usually a Protein
1. ENZYMES
2. ION CHANNELS
3. TRANSPORTERS
4. RECEPTORS
1. Enzymes – drug targets
• All Biological reactions are carried out under catalytic influence of enzymes – major drug target
• Drugs – increases/decreases enzyme mediated reactions
• In physiological system enzyme activities are optimally set
• Enzyme stimulation is less common by drugs – common by endogenous substrates – Pyridoxine (cofactor in decarboxylase activity)
– Adrenaline stimulates hepatic glycogen phosphorylase (hyperglycaemia)
• Enzyme inhibition – common mode of drug action
Enzymes – contd.
• Nonspecific inhibition: Denaturation of proteins –
strong acids, heavy metals, alkalies, alcohol, phenols
etc.
• Specific Inhibition:
Competitive Noncompetitive
What is specific enzyme inhibition?
• A drug may inhibit a
particular enzyme
without affecting
others and influence
that particular
substrate-enzyme reaction ultimately to
influence in the
product formation
Normal
Drug + Enzyme
Competitive Inhibition
Enzyme Inhibition - Examples
• Equilibrium: – Physostigmine Vs Acetylcholine (cholinesterase)
– Sulfonamides Vs PABA (folate synthetase)
– Moclobemide Vs Catecholamines (MAO-A)
– Captopril Vs Angiotensin 1 (ACE)
• Nonequilibrium: – Orgnophosphorous compounds/Nerve gases (cholinesterase)
• Non-competitive: – Acetazolamide (carbonic anhydrase), Omeprazole (HKATPase) ,
Aspirin (cyclooxygenase)
Effects of enzyme inhibition:
Normal Competitive (equilibrium)
2. Ion Channnel
• Proteins take part in transmembrane
signaling and regulates ionic composition
• Drugs also target these channels:
– Ligand gated channels
– G-protein operated channels
– Direct action on channels
• Examples
+ +
- -
+ +
--
- -
+ + + +
- -
Na+
+ + + +
- - - -
Resting (Closed**)
Open
(brief)
inactivated
Very slow repolarization in presence of LA
LA receptor
LA have highest affinity for the inactivated form
Refractory period
LA acting on Na+ receptors
3. Transporters
• Substrates are translocated across membrane by
binding to specific transporters (carriers) – Solute Carrier
Proteins (SLC)
• Pump the metabolites/ions I the direction of
concentration gradient or against it
• Drugs interact with these transport system
• Examples: Probenecid (penicillin and uric acid),
Furosmide (Na+K+2Cl- cotransport), Hemicholinium
(choline uptake) and Vesamicol (active transport of Ach
to vesicles)
4. Receptors
• Drugs usually do not bind directly with enzymes,
channels, transporters or structural proteins, but act
through specific macromolecules – RECEPTORS
• Definition: It is defined as a macromolecule or binding
site located on cell surface or inside the effector cell that
serves to recognize the signal molecule/drug and initiate
the response to it, but itself has no other function, e.g. G-
protein coupled receptor
Receptors – contd.
• Two essential functions:
– Recognition of specific ligand molecule
– Transduction of signal into response
• Two Domains:
– Ligand binding domain
– Effectors Domain – undergoes functional
conformational change
Some Definitions
• Agonist: An agent which activates a receptor to produce an effect
similar to a that of the physiological signal molecule, e.g. Muscarine
and Nicotine)
• Antagonist: an agent which prevents the action of an agonist on a
receptor or the subsequent response, but does not have an effect of
its own, e.g. atropine and muscarine
• Inverse agonist: an agent which activates receptors to produce an
effect in the opposite direction to that of the agonist, e.g. DMCM
• Partial agonist: An agent which activates a receptor to produce
submaximal effect but antagonizes the action of a full agonist, e.g.
pentazocine
• Ligand: any molecule which attaches selectively to particular
receptors or sites (only binding or affinity)
Some Definitions – contd.
• Affinity: Ability of a substrate to bind with
receptor
• Intrinsic activity (IA): Capacity to induce
functional change in the receptor
If explained in terms of affinity and IA:
• Agonist: Affinity + IA (1)
• Antagonist: Affinity + IA (0)
• Partial agonist: Affinity + IA (0-1)
• Inverse agonist: Affinity + IA (0 to -1)
D + R DR Complex
Affinity – Measure of propensity of a drug to bind
receptor; the attractiveness of drug and receptor
– Covalent bonds are stable and essentially irreversible
– Electrostatic bonds may be strong or weak, but are usually
reversible
Drug - Receptor Binding Affinity
Drug Receptor Interaction
DR Complex Effect (E)
Efficacy (or Intrinsic Activity) – ability of a bound drug
to change the receptor in a way that produces an
effect; some drugs possess affinity but NOT efficacy
Drug Receptor Interactions, The two-state model of receptor activation
(Resting state)
(Active state)
(Activated state)
The receptor is in two conformational states, ‗resting‘ (R) and ‗active‘ (R*), which exist in
equilibrium
Normally, when no ligand is present, the equilibrium lies far to the left, and a few receptors are
found in the R* state
For constitutively active receptors, an appreciable proportion of receptors adopt the R*
conformation in the absence of any ligand
Agonists have higher affinity for R* than for R and thus shift the equilibrium from the resting
state (R) to the active (R*) state and hence, produce a response
Drug Receptor Interactions, Inverse agonist
Inverse agonist ―An agent which binds to the same receptor
binding-site as an agonist for that receptor but
exerts the opposite pharmacological effect‖
Difference from Antagonist: Antagonist binds to the
receptor, but does not reduce basal activity
Agonist positive efficacy
Antagonist zero efficacy
Inverse agonist negative efficacy
Inverse agonists are effective against certain types
of receptors (e.g. certain histamine receptors and
GABA receptors) which have constitutive activity
Example 1: the agonist action of benzodiazepines on the benzodiazepine
receptor in the CNS produces sedation, muscle relaxation, and controls
convulsions. b-carbolines (inverse agonists) which also bind to the same receptor
cause stimulation, anxiety, increased muscle tone and convulsions
Example 2: the histamine H2 receptor has constitutive activity, which can be
inhibited by the inverse agonist cimetidine. On the other hand, burimamide acts
as a neutral antagonist
Drug Receptor Interactions, The two-state model of receptor activation & Inverse Agonist
Inverse Agonist Antagonist
(Resting state)
(Active state)
(Activated state)
An inverse agonist has higher affinity for R than for R* and thus will shift the
equilibrium from the active (R*) to resting state (R) state
A neutral antagonist has equal affinity for R and R* so does not by itself affect the
conformational equilibrium but reduces by competition the binding of other
ligands
In the presence of an agonist, partial agonist or inverse agonist, the
antagonist restores the system towards the constitutive level of activity
Drug Receptor Interactions, The two-state model of receptor activation & Inverse Agonist, contd.
An inverse agonist has higher affinity for R than for R* and thus will shift the
equilibrium from the active (R*) to resting state (R) state
A neutral antagonist has equal affinity for R and R* so does not by itself affect the
conformational equilibrium but reduces by competition the binding of other
ligands
In the presence of an agonist, partial agonist or inverse agonist, the
antagonist restores the system towards the constitutive level of activity
Drug-Receptor Bonds 1. Covalent Bond
-Very strong
-Not reversible under biologic conditions
unusual in therapeutic drugs
Example: phenoxybenzamine at a adrenergic
receptors
The rest of pharmacology is concerned with weak, reversible, electrostatic attractions:
2. Ionic bond
-Weak, electrostatic attraction between positive
and negative forces
-Easily made and destroyed
3. Dipole - dipole interaction
-A stronger form of dispersion forces formed by the
instantaneous dipole formed as a result of
electrons being biased towards a particular atom
in a molecule (an electronegative atom).
-Example: Hydrogen bonds
Drug-Receptor Bonds, contd.
4. Hydrophobic interactions
―The tendency of hydrocarbons (or of lipophilic
hydrocarbon-like groups in solutes) to form
intermolecular aggregates or intramolecular
interactions in an aqueous medium‖
-usually quite weak
-important in the interactions of highly lipid-
soluble drugs with the lipids of cell membranes
and perhaps in the interaction of drugs with the
internal walls of receptor ―pockets‖
5. Dispersion (Van der Waal) forces
-Attractive forces that arise between particles as
a result of momentary imbalances in the
distribution of electrons in the particles.
-These imbalances produce fluctuating dipoles
that can induce similar dipoles in nearby
particles, generating a net attractive force.
Drug-Receptor Bonds and Selectivity
Drugs which bind through weak bonds to their receptors are generally more
selective than drugs which bind through very strong bonds
This is because weak bonds require a very precise fit of the drug to its
receptor if an interaction is to occur
Only a few receptor types are likely to provide such a precise fit for a
particular drug structure
To design a highly selective short acting drug for a particular receptor, we
would avoid highly reactive molecules that form covalent bonds and instead
choose molecules that form weaker bonds
Selectivity:
Preferential binding to a certain receptor subtype leads to a greater effect at
that subtype than others
-e.g. salbutamol binds at β2 receptors (lungs) rather than at β1 receptors
(heart)
Lack of selectivity can lead to unwanted drug effects.
-e.g. salbutamol (b2-selective agonist ) vs isoprenaline (non-specific b-agonist) for
patients with asthma. Isoprenaline more cardiac side effects (e.g.,
tachycardia)
Receptors – contd.
• Cell surface receptors remain floated in cell membrane lipids
• Functions are determined by the interaction of lipophillic or hydrophillic domains of the peptide chain with the drug molecule
• Non-polar hydrophobic portion of the amino acid remain buried in membrane while polar hydrophilic remain on cell surface
• Hydrophilic drugs cannot cross the membrane and has to bind with the polar hydrophilic portion of the peptide chain
• Binding of polar drugs in ligand binding domain induces conformational changes (alter distribution of charges and transmitted to coupling domain to be transmitted to effector domain
Receptors – contd.
• Drugs act on Physiological receptors and
mediate responses of transmitters,
hormones, autacoids and others –
cholinergic, adrenergic or histaminergic
etc.
• Drugs may act on true drug receptors -
Benzodiazepine receptors
The Transducer mechanism
• Most transmembrane signaling is accomplished by a small number of different molecular mechanisms (transducer mechanisms)
• Large number of receptors share these handful of transducer mechanisms to generate an integrated response
• Mainly 4 (four) major categories: 1. GPCR
2. Receptors with intrinsic ion channel
3. Enzyme linked receptors
4. Transcription factors (receptors for gene expression)
Receptor Family Summary and Examples
1- Ligand-gated Ion Channels
They incorporate a ligand-binding (a receptor) site, usually in the
extracellular domain and they are activated by binding of a ligand (agonist)
to the receptor on the channel molecule.
Binding of the agonist causes a conformational change in the receptor
which leads to ion channel opening.
Involved in fast synaptic transmission
They control the fastest synaptic events in the nervous system, in which
neurotransmitter acts on the postsynaptic membrane of a nerve or muscle cell
and transiently increases its permeability to particular ions
Example: nACh
receptor
2. G-protein-Coupled Receptors (GPCRs)
The largest family: G-protein (guanine nucleotide binding regulatory
proteins) families: Gs ,Gi and Gq
Examples: mAChR, adrenoceptors, glutamate receptors, GABAB receptors
Actions: fast (seconds)
Structure:
GPCR consists of seven transmembrane a-helices
G-protein consists of 3 subunits, a, b, g.
Guanine nucleotides bind to the a-subunit which has enzymatic activity (GTP GDP)
The b and g subunits remain together as b, g-complex
2. G-protein-Coupled Receptors
―The activation of the effector tends to be self-limiting‖?? ------GTPase
Amplification?
Mechanism: binding of the agonist to the
GPCR activation of the GPCR G-
protein activation (G-GDP G-GTP) :
activation of enzyme with subsequent
generation of second messengers (e.g.
cAMP, IP3) → biological effect or
opening or closing of an ion channel
(Inactive) (Active)
Opposite functional effects may be produced at the same cell type by GPCRs (e.g.,
mAChR and b-adrenoceptors in cardiac cells)
2. G-protein-Coupled Receptors, Effectors
PIP2:
phosphatidylinositol-
4,5-bisphosphate
IP3:
inositol-1,4,5-
trisphosphate
DAG:
1,2-diacylglycerol
PIP2
Gq
G-proteins and Effectors
• Large number can be distinguished by
their α-subunits
G protein Effector pathway Substrates
Gs Adenylyl cyclase Beta-receptors, H2, D1
Gi Adenylyl cyclase Muscarinic M2
D2, alpha-2
Gq Phospholipase C Alph-1, H1, M1, M3
Go Ca++ channel Potassium channel in heart,
smooth muscle
Common intracellular signaling proteins
b) Protein kinases: modulate the activity or the binding
properties of substrate proteins by phosphorylating
serine, threonine, or tyrosine residues.
The phosphorylated form of some proteins is
active, whereas the dephosphorylated form of
other proteins is active.
The combined action of kinases and
phosphatases can cycle proteins between active
and inactive states.
(a) GTP-binding proteins with GTPase activity function
as molecular switches.
When bound to GTP they are active; when
bound to GDP, they are inactive.
They fall into two categories, trimeric G proteins
and Ras-like proteins.
c) Adapter proteins contain various protein-binding
motifs that promote the formation of multiprotein
signaling complexes.
3. Kinase-linked Receptors, General structure &
activation of receptor tyrosine kinases
Tyrosine-kinase (called receptor tyrosine kinase, more common) and guanylate cyclase-
linked (much less common) receptors
Actions: take minutes
Examples: Growth factors, hormones (e.g.
insulin) and cytokines
Receptors for various hormones (e.g., insulin)
and growth factors possess tyrosine kinase
activity in their intracellular domain.
The intracellular domain incorporates both ATP-
and substrate binding sites
Cytokine receptors do not usually have intrinsic
kinase activity, but associate, when activated by
ligand binding, with kinases known as Jaks,
which is the first step in the kinase cascade
Kinase-linked Receptors, General structure and activation of receptor tyrosine kinases
The ligands for some RTKs, such as the receptor for
EGF, are monomeric; ligand binding induces a
conformational change in receptor monomers that
promotes their dimerization.
The ligands for other RTKs are dimeric; their binding
brings two receptor monomers together directly.
In either case, upon ligand binding, a tyrosine kinase
activity is ―switched on‖ at the intracellular portion.
the kinase activity of each subunit of the dimeric
receptor initially phosphorylates tyrosine residues
near the catalytic site in the other subunit.
Subsequently, tyrosine residues in other parts of the
cytosolic domain are autophosphorylated.
Protein phosphorylation leads to altered cell function
via the assembly of other signal proteins
Kinase-linked Receptors, Activation of Ras following binding of a
hormone (e.g., EGF) to an RTK.
1. The adapter protein GRB2 binds to a specific
phosphotyrosine on the activated RTK and to
Sos, which in turn interacts with the inactive
Ras·GDP.
2. The guanine nucleotide – exchange factor
(GEF) activity of Sos then promotes formation
of active Ras·GTP.
Note that Ras is tethered to the membrane by a farnesyl anchor
Kinase-linked Receptors, Kinase cascade that transmits signals
downstream from activated Ras protein
1. Activated Ras binds to the N-terminal domain of
Raf, a serine/threonine kinase.
2. Raf binds to and phosphorylates MEK, a dual-
specificity protein kinase that phosphorylates
both tyrosine and serine residues.
3. MEK phosphorylates and activates MAP
kinase, another serine/threonine kinase.
4. MAP kinase phosphorylates many different
proteins, including nuclear transcription factors,
that mediate cellular responses.
3. Kinase-linked Receptors, Growth Factor Receptors
Activation of Ras
GDP/GTP Exchange
Activation
Binding of SH2-domain protein (Grb2)
Tyrosine
residue
Conformation
change
Dimerisation
Tyrosine
autophosphrylation
Phosphorylation
of Grb2
Raf
Mek
MAP kinase
Various transcription factors
GTP
NUCLEUS
Gene Transcription
Agonist binding leads to dimerisation and autophosphorylation of the intracellular domain of each receptor
SH2 domain proteins, Grb2, then bind to the phosphorylated receptor and are themselves phosphorylated
Ras, which is a proto-oncogene product, functions like a G-protein, and conveys the signal (by GDP/GTP exchange) Grb
Activation of Ras in turn activates Raf, which is the first of a sequence of three kinases, each of which phosphorylates, and activates, the next in line
The last of these, mitogen-activated protein (MAP) kinase, phosphorylates one or more transcription factors that initiate gene expression, resulting in a variety of cellular responses, including cell division
Ras
Grb2
Grb2
MEMBRANE
Cytokine binding leads to receptor
dimerisation, and this attracts a cytosolic
tyrosine kinase unit (Jak) to associate with,
and phosphorylate, the receptor dimer
Among the targets for phosphorylation by Jak
are a family of transcription factors (Stats)
which bind to the phosphotyrosine groups on
the receptor-Jak complex, and are
themselves phosphorylate
Thus activated, Stat migrates to the nucleus
and activates gene expression
3. Kinase-linked Receptors, Cytokine Receptors
NUCLEUS
Gene Transcription
Stat
Stat Stat
Jak Jak Jak Jak
Binding &
phosphorylation
of SH2-domain
protein (Stat)
MEMBRANE
4. Intracellular Receptors
These receptors could be cytosolic or nuclear
Several biologic signals are sufficiently lipid-soluble to cross the plasma
membrane and act on intracellular receptors.
One of these is a gas, nitric oxide (NO), that acts by stimulating an intracellular
enzyme, guanylyl cyclase, which produces cyclic guanosine monophosphate
(cGMP), which stimulates a cGMP-dependent protein kinase.
Another class of ligands—including corticosteroids, mineralocorticoids, sex
steroids, vitamin D, and thyroid hormone—stimulates the transcription of genes
in the nucleus by
binding to nuclear receptors
This binding of hormone exposes a normally hidden domain of the receptor
protein, thereby permitting the latter to bind to a particular nucleotide sequence
on a gene and to regulate its transcription.
End result is an alteration in gene transcription and therefore protein synthesis
Actions: slow-acting (hours), long lasting
Nuclear Receptors, an example
Mechanism of glucocorticoid
action.
A heat-shock protein, hsp90,
binds to the glucocorticoid
receptor polypeptide in the
absence of hormone and
prevents folding into the active
conformation of the receptor.
Binding of a hormone ligand
(steroid) causes dissociation of
the hsp90 stabilizer and permits
conversion of glucocorticoid
receptor to the active
configuration.
The active glucocorticoid receptor binds to a particular nucleotide
sequence on a gene altered
transcription of certain genes
Dose-Response Relationship
• Dose-plasma concentration
• Plasma concentration (dose)-response
relationship
Dose-Response Curve
dose Log dose
% r
esponse
% r
esponse
100% 50%
100% 50%
Dose-Response Curve
• Advantages:
– A wide range of drug doses can easily be
displayed on a graph
– Potency and efficacy can be compared
– Comparison of study of agonists and
antagonists become easier
Potency and efficacy
• Potency: It is the amount of drug required to produce a
certain response
• Efficacy: Maximal response that can be elicited by a drug
Response
Drug in log conc.
1 2 3 4
Therapeutic index (TI)
• Therapeutic Index = Median Lethal Dose (LD50) Median Effective dose (ED50)
Idea of margin of safety Margin of Safety
Therapeutic index (TI)
• It is defined as the gap between therapeutic effect DRC
and adverse effect DRC (also called margin of safety)
Therapeutic Index, contd.
Why don’t we use a
drug with a T.I. <1?
ED50 > TD50 = Very Bad!
• High therapeutic index
– NSAIDs
• Aspirin
• Tylenol
• Ibuprofen
– Most antibiotics
– Beta-blockers
• Low therapeutic index
– Lithium
– Neuroleptics
• Phenytoin
• Phenobarbital
– Digoxin
– Immunosuppressives
Therapeutic Index (T.I.)
Combined Effects of Drugs
• Drug Synergism – Additive effect (1 + 1 = 2)
• Aspirin+paracetamol, amlodipine+atenolol
– Supraadditive effect (1 + 1 = 4) • Sulfamethoxazole+trimethoprim, levodopa+carbidopa,
acetylcholine+physostigmine
• Drug Abntagonism: 1. Physical: Charcoal
2. Chemical: KMNO4, Chelating agents
3. Physiological antagonism: Histamine and adrenaline in bronchial asthma, Glucagons and Insulin
4. Receptor antagonism
Antagonists, Overview
Definition
―An antagonist is a substance that does
not provoke a biological response itself,
but blocks or reduces agonist-mediated
responses‖
Antagonists have affinity but no
efficacy for their cognate receptors
Binding of antagonist to a receptor will
inhibit the function of a partial agonist,
an agonist or inverse agonist at that
receptor
Antagonists mediate their effects by binding to the active site or to allosteric
sites on receptors or they may interact at unique binding sites not normally
involved in the biological regulation of the receptor's activity.
Antagonist activity may be reversible or irreversible depending on the longevity
of the antagonist–receptor complex which in turn depends on the nature of
antagonist receptor binding.
• Receptor antagonism:
1. Competitive antagonism (equilibrium)
2. Competitive (non equilibrium)
3. Non-competitive antagonism
Drug antagonism DRC
Drug antagonism DRC – non-
competitive antagonism Response
Shift to the right and lowered response
Drug in log conc.
Agonist Agonist + CA (NE)
Antagonists, 1-Competitive reversible antagonist
It binds to same site on receptor as agonist
inhibition can be overcome by increasing
agonist concentration (i.e., inhibition is
reversible)
No significant depression in maximal response
(Emax ??)
The agonist dose-response curve will be
shifted to the right (without a change in the
slope of the curve)
Maximal response occurs at a higher agonist
concentration than in the absence of the
antagonist
It primarily affects agonist potency
Clinically useful
Example: Prazosin at a adrenergic receptors
Agonist Antagonist +
Agonist
EC50A EC50B
Antagonists, 1-Competitive reversible antagonist
It binds to same site on receptor as agonist
inhibition can be overcome by increasing
agonist concentration (i.e., inhibition is
reversible)
No significant depression in maximal response
(Emax ??)
The agonist dose-response curve will be
shifted to the right (without a change in the
slope of the curve)
Maximal response occurs at a higher agonist
concentration than in the absence of the
antagonist
It primarily affects agonist potency
Clinically useful
Example: Prazosin at a adrenergic receptors
Antagonists, 2- Competitive irreversible antagonist
It binds to same site on receptor as agonist
The antagonist possesses reactive group
which forms covalent bond with the receptor
the antagonist dissociates very slowly, or
not at all
inhibition cannot be overcome by increasing
agonist concentration (i.e., inhibition is
irreversible)
Maximal response is depressed (i.e., Emax is
decreased)
The agonist dose-response curve will be shifted
to the right (the slope of the curve will be
reduced)
Agonist potency may or may not be affected
The only mechanism the body has for overcoming the block is to synthesize new receptors
Experimental tools for investigating receptor functions
Example: phenoxybenzamine at a adrenergic receptors
Competitive reversible antagonist vs Competitive irreversible antagonist
Antagonists, contd.
Antagonist Receptor
Antagonist-Receptor
Complex
DENIED!
Competitive Antagonists, In Motion
Antagonists, 3- Non-competitive antagonist It does not bind to the same receptor sites as
the agonist. It would either:
bind to a distinctly separate binding site from the
agonist decreased affinity of the receptor for the
agonist, ―allosteric inhibition‖, So, it prevents conformational changes in the
receptor required for receptor activation after the
agonist binds ―allosteric inhibition‖,
or alternatively block at some point the chain of
events that leads to the production of a response by
the agonist
Inhibition cannot be overcome by increasing
agonist concentration (irreversible)
Agonist maximal response will be depressed
Agonist dose-response curve will be shifted to
the right (the slope of the curve will be reduced)
Agonist potency may or may not be affected
Agonist
Antagonist
+ Agonist
Example: the noncompetitive antagonist action of crystal violet (CrV) on nicotinic
acetylcholine receptors is explained by an allosteric mechanism in which the binding
of CrV to the extracellular mouth of the resting receptor leads to an inhibition of
channel opening
Agonist Receptor
Antagonist
‘Inhibited’-Receptor DENIED!
Non-competitive Antagonist, In Motion
Antagonists, contd.
4. Physiologic (functional) antagonist
Physiologic antagonism occurs when the actions of two agonists working at
two different receptor types have opposing (antagonizing) actions
Example 1: Histamine acts at H1 receptors on bronchial smooth muscle to cause
bronchoconstriction, whereas adrenaline is an agonist at the β2 receptors bronchial
smooth muscle, which causes bronchodilation.
Example 2: histamine acts on receptors of the parietal cells of the gastric mucosa to
stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton
pump
5. Chemical antagonist
Chemical antagonism occurs when two substances combine in solution
the active drug is lost
Example : Chelating agents (e.g., dimercaprol) that bind heavy metals, and thus
reduce their toxicity
6. Pharmacokinetic antagonist
Pharmacokinetic antagonist effectively reduces the concentration of the
active drug at its site of action
Example: phenobarbital accelerates the rate of metabolic degradation of warfarin