PHARMACOLOGY
Ion channels, receptors,
agonists and antagonists
Cameron J Weir
Abstract
This article describes the physiology of ion channels and the principal
molecular mechanisms responsible for modulating their activity by
commonly used drugs in anaesthesia and intensive care. The concept
of efcient and selective transport of ions across impermeable
plasma membranes is introduced, together with the mechanisms inu-
encing electrochemical signalling within cells. The classication and
composition of voltage-gated ion channels are described in the
context of their contribution to action potential generation in excitable
cells. Drugereceptor interaction of the four main classes of receptor,
that is, ligand-gated ion channels (in particular Cys-loop channels),
G-protein-coupled, enzyme-linked and nuclear receptors, are
described together with an overview of the various signal-
transduction mechanisms adopted by metabotropic receptors to con-
trol cellular function. Finally, the principles of drugereceptor interac-
tion of agonists, antagonists and inverse agonists are discussed in
relation to their afnity, efcacy and potency.
Keywords G-protein-coupled receptors; inverse agonists; ligand-
gated ion channels; voltage-gated ion channels
Royal College of Anaesthetists CPD matrix: 1A02
Ion channels
Electrical signalling across lipid membranes is essential for
communication within and between cells. However, cell mem-
branes are densely packed phospholipid structures and normally
act as impenetrable barriers to permanently charged molecules.
To overcome this problem, Nature developed the machinery to
selectively transport charged particles across electrically-insu-
lated membranes in order to facilitate the important physiolog-
ical role of ionic communication. In some cases, ions may be
carried across membranes by energy-dependent transporters, but
this relatively slow process is limited by the maximal turnover
rate of the transporter. A much more rapid and efficient system
uses large, membrane-bound glycoproteins, containing water-
filled pores (ion channels) together with established electro-
chemical gradients between the extra- and intracellular com-
partments. The activation, or gating, of an ion channel results in
the rapid, but selective, movement of ions across a plasma
membrane. Movement of positively charged ions (cations) into,
or negatively charged ions (anions) out of, a cell produces de-
polarization (or excitation), whereas hyperpolarization
Cameron J Weir PhD FRCA is Consultant Anaesthetist and Honorary
Senior Clinical Lecturer at Ninewells Hospital and Medical School,
Dundee. Conicts of interest: none declared.
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Learning objectives
After reading this article, you should be able to:
C describe the range of molecular targets for drugs used in
anaesthesia and intensive care
C appreciate the mechanisms underlying their pharmacological
effects
C understand basic receptor classification and the principles of
drugereceptor interaction
(inhibition) of cellular function is brought about by the opposite
effect (i.e. movement of negative charges into, or positive
charges out of, the cell). The ubiquitous, but diverse nature of
ion channels is reflected in the wide range of important biological
functions they perform, including cell excitation, muscle
contraction and intracellular signalling. In simple terms, ion
channels are classified according to the stimulus required to
open, or gate the channel. Many different stimuli exist,
including neurotransmitters, drugs, alteration of hydrogen ion
concentration, temperature and mechanical pressure. However,
this review will limit discussion to ion channels activated by
neurotransmitters (ligand-gated), or to changes in local mem-
brane potential (voltage-gated).
Ligand-gated ion channels
Ligand-gated ion channels are multimeric proteins constructed
from large glycoprotein subunits. They are activated by a
chemical (agonist) binding to a distinct site or sites within the
channel complex. In most cases, neurotransmitters released from
presynaptic neurones serve as the primary agonists, acting as
part of a complex integrated process required for rapid (milli-
second timescale) neuronal communication. Binding of the
neurotransmitter to the protein induces a conformational change,
resulting in the opening of the integral ion channel. The charge
and the direction of ion flux through the activated channel
determine its effect on cellular function (i.e. depolarization or
hyperpolarization).
Fast excitatory neurotransmission within the central nervous
system (CNS) is mediated principally by ionotropic glutamate
receptors whereas a superfamily of genetically related ligand-
gated ion channels (cysteine loop) is responsible for the major-
ity of fast inhibitory neurotransmission (g-aminobutyric acid
receptor type A (GABAA) and glycine receptors) and, to some
extent, excitatory neurotransmission (nicotinic acetylcholine
(nACh) and 5-hydroxytryptamine type 3 (5HT3) receptors)
(Figure 1). Ionotropic (integrally linked to an ion channel) as
opposed to metabotropic (indirectly linked to ion channels via
signalling cascade mechanisms) glutamate receptors are impor-
tant for neuronal excitation and have been implicated in many
important physiological and pathological roles including
learning, memory and neurodegeneration. Glutamate receptor
subtypes are named according to their preferred synthetic ago-
nists (e.g. N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-
methyl-4-isoxazole proprionic acid (AMPA) and kainate). Acti-
vation of glutamate-gated ion channels initiates the movement of
cations (mainly Na and Ca2) into the cell which results in an
1 2016 Published by Elsevier Ltd.
 PHARMACOLOGY
Ligand-gated ion channels
GABA A Glycine
Cl Cl
Extracellular
Cl 125 mM
Na+ 145 mM
Ca2+ 2 mM
K+ 4 mM
Intracellular
Cl 5 mM
Na+ 12 mM
Ca 2+ 0.1 mM
K+ 140 mM
Hyperpolarization
(~inhibition)
Ligand-gated ion channels (LGICs) mediate the majority of fast neurotransmission within the CNS. Fine tuning of CNS activity is achieved
by modulating the activity of inhibitory and excitatory LGICs. Many clinically useful neuroactive drugs alter the activity of LGICs.
5-HT, 5 hydroxytryptamine; AMPA, -amino-3-hydroxy-5-methyl-4-isoazole proprionic acid; GABAA, -aminobutyric acid receptor type
A; NMDA, N-methyl-D-asparate
Figure 1
excitatory post-synaptic current. If this current has sufficient
amplitude, an action potential may be generated. The so-called
Cys-loop family of receptors (characterized by a conserved
cysteineecysteine bridge within the extracellular portion of the
receptor) mediates a variety of important physiological functions
by finely tuning the balance of excitatory and inhibitory activity
within the CNS. Most classes of ligand-gated ion channels are
susceptible to modulation by drugs used in anaesthesia and
intensive care medicine, including general anaesthetics, anxio-
lytics, anti-emetics and neuromuscular blockers.
Receptor topology: Cys-loop ion channels are composed of five
membrane-spanning subunits arranged around a central aqueous
pore (Figure 2). Each class of receptor has its own pool of sub-
units. For example, GABAA receptors are composed of five sub-
units taken from a pool of 19 possible subtypes, including a1e6,
b1e3, g1e3, r1e3, d, 3, p and q. Subunits are constructed from
approximately 450 amino acids which fold into a large extracel-
lular domain and four transmembrane domains. The large
extracellular domain contains the agonist (e.g. acetylcholine,
GABA, glycine) binding site for each channel. The second
transmembrane (TM2) domain from each subunit faces into the
centre of the protein to line the surface of the aqueous pore or
channel. The physicochemical properties (e.g. size and charge)
of the amino acids within the TM2 region together with their
location within the channel provide the ideal conditions for
selectively filtering cations or anions during channel opening.
Ionotropic glutamate receptors are composed of four subunits
each with three transmembrane domains and a re-entrant loop
that contributes to the lining of the channel pore. Glutamate
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Nicotinic acetylcholine Glutamate 5-HT3
(NMDA/AMPA/Kainate)
Na+ (Ca 2+) Na+ (Ca 2+) Na+ (Ca2+)
K+ K+ K+
Depolarization
(~excitation)
receptor subtypes are drawn from a pool of subunits as follows:
NMDA receptors (NR1, NR2A, NR2B, NR2C, NR2D, NR3A and
NR3B); AMPA receptors (A1eA4) and kainate receptors (K5eK7).
Ligand-gated ion channel modulation: ligand-gated ion chan-
nels are susceptible to modulation by many clinically useful
classes of drugs. The inhibitory GABAA receptor is rather pro-
miscuous in this respect because it is sensitive to the modulatory
effects of a range of chemically diverse agents, including ben-
zodiazepines, barbiturates and general anaesthetics. The mech-
anisms underpinning the pharmacology of benzodiazepines have
received much attention in recent years. It now seems that some
of their clinical effects can be mapped not only to individual
subunits, but also to single amino acids within them. Genetically
engineered mice harbouring single amino acid mutations within
GABAA receptor subunits are selectively resistant to some of the
clinical properties of diazepam. For example, the anxiolytic ef-
fects of diazepam appear to be mediated by the a2-subunit,
whereas the sedative effects are mainly mediated by the a1-
subunit. Similar research using intravenous general anaesthetics
in mice demonstrates that the sedative and hypnotic effects of
etomidate are mediated by b2- and b3-subunit-containing GABAA
receptos, respectively. Moreover, it seems that the cardiorespi-
ratory depressant effects of some of the intravenous anaesthetics
are also mediated by GABAA receptors containing b2- and b3-
subunits.
Voltage-gated ion channels
Voltage-gated ion channels, as their name suggests, are activated
by changes to the local membrane potential. Three clinically
2 2016 Published by Elsevier Ltd.
 PHARMACOLOGY

NH2
Cys-loop ion channel topology
Agonist
S COOH

1 2 3 4

Most ligand-gated ion channels are oligomeric proteins containing five subunits. Individual
subunits are formed from a sequence of amino acids that fold into a large extracellular domain and four
transmembrane (TM) spanning regions. The TM2 region faces into the ion channel to line its surface

Figure 2

important channels selectively permeable to potassium (K),
sodium (Na) and calcium ions (Ca2) are described below.
Voltage-gated ion channel topology: K channels are primarily
composed of single subunits containing a variable number of
transmembrane and pore-forming regions. Some K channels
probably exist as dimers (4TM family) or tetramers (2TM and
6TM families). To date, more than 70 different K channel sub-
types have been identified. In contrast, the a-subunit within
voltage-gated Na and Ca2 channels is composed of four iden-
tical regions (IeIV), each containing six transmembrane domains
(S1eS6) (Figure 3). The voltage-sensing region contains mainly

Voltage-gated sodium channel topology (-subunit)

I II III IV

+ +
+ +
a 1 2 34 5 6 1 2 34 5
+ +
+ +
+ +
+ +
6 1 2 34 5 6 1 2 34 5 6
+ +
+ +

NH2
COOH

Na+
II II

I III I III

b IV IV
Closed/active Open

Courtesy of Professor JA Peters, University of Dundee

Figure 3

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 PHARMACOLOGY
positively charged amino acids and is located within the S4
segment. Quaternary folding of the protein produces a ring-
shaped molecule, with the amino acids between the S5 and S6
segments contributing to the internal channel pore. In the closed
state a mobile intracellular loop joining regions IIIeIV serves as
an electromechanical block to close, or inactivate, the channel.
K channels are important regulators of cellular excitability
because of their influence on the resting membrane potential and
on the frequency and duration of the action potential. For
example, certain voltage-gated K channel subtypes are activated
in the early phase of the action potential and produce a slow, but
sustained outward K current. This slow outward current
counteracts the rapid inward Na current and brings the mem-
brane potential back towards the resting membrane potential.
Alteration of K channel function will, therefore, have a pro-
found effect on action potential kinetics. For example, inherited
K channel mutations contribute to a range of neurological and
cardiac diseases, including the life-threatening long QT syn-
drome. K channel nomenclature is broadly based on the num-
ber of transmembrane domains and pores present within the
protein. Channels containing six transmembrane domains and a
single pore (6T1P) are particularly sensitive to changes in voltage
and intracellular calcium concentrations (Kv1.xeKv3.x, Kv7.x,
Kv10.xeKv12.x, KCa1-5x), whereas channels composed of two
transmembrane domains and a single pore (2T1P; inward recti-
fying) are regulated mainly by G-proteins and intracellular
adenosine triphosphate (ATP) levels. Two pore domain K
channels (4T2P; outward rectifying) contribute to a resting K
current and some subtypes (i.e. TREK and TASK) are particularly
sensitive to potentiation by volatile anaesthetic agents.
Na channels: under normal conditions the resting membrane
potential of excitable cells is maintained at approximately
70 mV by a constant outward leak of K. Small positive shifts
of the membrane potential, beyond a threshold of approximately
55 mV, result in the simultaneous opening of Na channels.
Channel opening results in a rapid inward movement of Na,
causing membrane depolarization to approximately 40 mV.
Nine different subtypes of Na channel have been identified on
the basis of the nature of the pore-forming a-subunit (Nav1.1
eNav1.9), their sensitivity to the Na channel blocker tetrodo-
toxin and their different rates of channel inactivation. Most
clinically relevant voltage-activated Na channel subtypes are
located in neurones, and cardiac and skeletal muscle. Na
channels are susceptible to blockade by local anaesthetics, some
anticonvulsants and some antidysrhythmic drugs. Local anaes-
thetics, in particular lidocaine, preferentially bind to and stabilize
the inactivated channel conformation and so prolong the dura-
tion of the refractory period between action potentials. Unfortu-
nately, the lack of subtype specificity of local anaesthetic drugs
results in a low therapeutic index and a number of unwanted side
effects, including negative inotropic activity (blockade of Nav1.5
channels in myocardial tissue and seizures (Nav1.1eNav1.3 in
the brain)).
Ca2 channels: Ca2 ions are ubiquitous, but essential mediators
of many important cellular processes, including neurotransmitter
release and intracellular signalling. Ca2 concentrations are
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regulated by a variety of pathways, many of which are closely
integrated to ensure precise control of free intracellular calcium.
G-protein-coupled receptors (via cyclic adenosine mono-
phosphate (cAMP) and inositol triphosphate (IP3)), ligand-gated
channels (via NMDA receptors) and energy-dependent Ca2
transporters (Na/Ca2 exchange and Ca2 ATPase) also
contribute towards the regulation of Ca2 flux across plasma
membranes. Voltage-gated ion channels are present in most
excitable cells. They are composed of five major subtypes (L, N,
T, P/Q and R) based on their electrophysiological characteristics
and on their sensitivity and selectivity to antagonists. L-type
channels, incorporating the pore-forming Cav1.1eCav1.4 subunit,
are perhaps the most clinically relevant because they mediate
Ca2+-related events in smooth and cardiac muscle and their
subtypes are selectively blocked, albeit to varying degrees, by
dihydropyridine antagonists (e.g. nifedipine, verapamil and dilti-
azem). T-type channels (Cav3.1eCav3.3) contribute to pace-
maker activity in atrial and vascular smooth muscle and can be
selectively blocked by mibefradil (withdrawn due to interaction
with other drugs that prolong the QT interval). To date, no clin-
ically useful antagonists have been introduced for the remaining
three subtypes (N, Cav2.2; P/Q, Cav2.1 and R, Cav2.3).
Receptors
Paul Ehrlich (1854e1915) first proposed the concept of highly
specific interactions between drugs and receptors: corpora non
agunt nisi fixata (drugs do not act unless they are bound).
However, before discussing drug interaction, it is important to
clarify the definition of a receptor. To a pharmacologist, a re-
ceptor is a protein that recognizes an endogenous chemical
mediator such as a neurotransmitter, hormone or inflammatory
mediator. When the mediator (agonist) binds to the receptor, a
series of reactions takes place, ultimately leading to a change of
function of the host cell. For example, the binding of GABA to
GABAA receptors inhibits neuronal function by inducing an in-
ward flow of chloride ions (Cl) through an integral ion channel.
Often the term receptor is used loosely to describe a target
whose function is altered by an exogenous drug rather than an
endogenous mediator. For example, voltage-gated Na channels
have been described as local anaesthetic receptors, but the local
anaesthetic drug does not mediate a normal physiological pro-
cess. In this case, the Na channel may be more appropriately
labelled a drug target.
Receptor classication
In simple terms receptors can be classified into four categories
(Figure 4):
 ligand-gated ion channels
 G-protein-coupled receptors
 enzyme-linked receptors
 nuclear receptors.
G-protein-coupled receptors (GPCRs): G-protein-coupled re-
ceptors (GPCRs) form the largest single category of receptors
that mediate physiological functions, ranging from olfaction to
regulation of the autonomic nervous system. More than 1000
subtypes of GPCRs have been identified, including muscarinic
acetylcholine, adreno- and chemokine receptors. As a
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 PHARMACOLOGY
Receptor classification
Ligand-gated channels G-protein-coupled receptors
Ions
Enzyme Gi Gs
GTP C GTP
Second
messenger
Depolarization/ Change in [Ca2+]
hyperpolarization Protein kinase activity
Timescale
Fast (milliseconds)
G-protein (Gi inhibitory, Gs stimulatory) Drug
GTP, guanosine triphosphate
Figure 4
consequence of their ubiquitous distribution and functional
characteristics, GPCRs act as principal targets for approxi-
mately 60% of all prescribed drugs. Activation of GPCRs initi-
ates a cascade of intracellular signalling mechanisms, a process
which relies on intermediary G-proteins designed to link the
signal between agonist binding and activation of target en-
zymes or channels (effectors). GPCRs are composed of
approximately 400 amino acid residues folded into seven
transmembrane domains (Figure 4). The agonist-binding sites
are located within either the extracellular N-terminal domain
(e.g. peptide receptors) or the transmembrane regions (e.g.
receptors recognizing small amines). An intracellular loop of
variable length between TM5 and TM6 provides an anchoring
point for diffusible G-proteins. G-proteins are membrane-
associated trimeric complexes composed of one a-subunit and
a bg-dimer. Before receptor activation, a single guanosine
diphosphate (GDP) molecule is coupled to the a-subunit.
Agonist activation of the receptor induces a series of confor-
mational changes, resulting in an increased affinity of the GPCR
for the G-protein. The G-protein binds to the intracellular loop
of the receptor and simultaneously exchanges GDP for guano-
sine triphosphate (GTP), which triggers the dissociation of the
G-protein into a- and bg-subunits. The newly liberated a- and
bg-subunits are then free to activate the relevant effector en-
zymes or ion channels. The reaction is terminated after GTP is
hydrolysed to GDP by the inherent GTPase activity of the a-
subunit, and the a- and bg-subunits re-assemble into their
parent G-proteins. The beauty of GPCR signalling lies with the
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Enzyme-linked receptors Nuclear receptors
N
Enzyme
C
Second
messenger Phosphorylation
Gene transcription/protein synthesis
Slow (hours)
range of different G-protein isoforms available for interaction
with receptor/effector systems and the subsequent multi-
stepped cascade of enzyme-mediated events. Such a system
allows for not only specificity, but also amplification of the
receptor transduction signal.
Second messengers
 The enzymes responsible for the generation of second
messengers are the principal targets for GPCRs, for
example, adenylyl cyclase (cAMP), phospholipase C,
inositol triphosphate (IP3) and diacylglycerol (DAG). In
addition, voltage-gated ion channels (including K, Ca2
and Na channels) are directly modulated by the bg-sub-
unit of certain G-proteins.
 Adenylyl cyclase is a ubiquitous membrane-bound enzyme
that catalyses the conversion of ATP into cAMP. Most of
the biological effects of cAMP are mediated by the activa-
tion of protein kinase A and subsequent phosphorylation
events. However, direct modulation of hyperpolarization-
activated, cyclic nucleotide-gated (HCN) ion channels is
also well documented. cAMP levels are controlled by two
G-protein isoforms (Gs and Gi), which stimulate and
inhibit adenylyl cyclase activity, respectively. In addition,
cAMP is inactivated following conversion to 5AMP by
phosphodiesterase enzymes susceptible to inhibition by
theophyllines. Cholera toxin produces hypersecretion
within the gastrointestinal tract by stimulating Gs, whereas
pertussis toxin uncouples Gi and Go isoforms from their
GPCRs.
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 PHARMACOLOGY

 Phospholipase C/IP3: the Gq isoform of G-proteins facili-
tates the production of two important second messengers
from membrane phospholipids: IP3 and DAG. Gq activates
phospholipase C, the enzyme responsible for the catalytic
conversion of phosphatidylinositol 4,5-bisphosphate into
IP3 and DAG. IP3 is a water-soluble agonist for a ligand-
gated channel (IP3R), the principal mediator of GPCR-
induced Ca2 release from intracellular stores. In
contrast, DAG is a membrane-bound second messenger,
which activates one of 10 different isoforms of protein ki-
efficacy describes the ability of the drug to activate the receptor
once it has bound. Full agonists are capable of producing a
maximal response or maximal efficacy (this may occur when
only a fraction of receptors are occupied, hence the concept of
spare receptors), whereas partial agonists are not capable of
producing a full response even in the presence of high concen-
trations of agonist (Figure 5):
k1 b
A R # AR#AR / Effect
k1 a

nase C. Inactivation of the inositol phosphate system is
brought about by metabolism of IP3 and DAG by a com-
bination of phosphorylation (kinases) and dephosphory-
lation (phosphatases).
Enzyme-linked receptors: enzyme-linked receptors are
composed of approximately 1000 amino acid residues arranged
into a large extracellular domain, a single transmembrane region
and a variable-length intracellular domain (Figure 4). Enzyme-
linked receptors mediate the actions of various proteins
involved in tissue repair, defence and growth (e.g. insulin, in-
flammatory cytokines and growth factors). One of the defining
features of this class of receptor is the presence of specific en-
zymes, usually kinases, within the intracellular domain. On
ligand binding, many receptors undergo dimerization (coupling
of two receptors into one large complex) which, in many cases,
facilitates the autophosphorylation of tyrosine, serine or thre-
onine residues on each receptor. The phosphorylated residues
can then attract specific SH2 (Src homology) proteins and en-
zymes to alter cellular function through changes in gene tran-
scription. An alternative mechanism adopted by atrial natriuretic
factor uses enzyme-linked receptors containing intrinsic guanylyl
cyclase activity to modulate the activity of the cardiovascular
system.
Nuclear receptors: nuclear receptors form a small number of
important targets regulating the activity of many diverse agents,
including steroids and fat-soluble vitamins. In contrast to the
where: A is the agonist (or drug), R is the receptor, AR is the
bound receptor, AR* is the activated receptor, b and a are the
receptor activation and deactivation constants, respectively. In
the clinical setting measurement of affinity and efficacy is prob-
lematic because a drug might produce its effects by altering a
combination of physiological parameters. For example,
epinephrine increases blood pressure by increasing the rate and
force of contraction of the heart (b-adrenoreceptors) but also
causes profound vasoconstriction (a-adrenoreceptors). There-
fore, the term potency has been adopted as a measure of the
concentration of a drug required to produce a particular
response, usually 50% of the maximal possible response (effec-
tive concentration; EC50). Highly potent drugs will have smaller
EC50s than less potent drugs (Figure 5).
Antagonists
Competitive receptor antagonists are classed as either reversible
or irreversible. Competitive antagonists bind to the receptor and
therefore possess affinity, but they are unable to produce a
response and thus lack efficacy. Furthermore, they prevent the
agonist from binding and so block its ability to activate the
receptor:
Agonist concentrationresponse curves
Increasing Potency Decreasing
100

Increasing
receptors described previously, the so-called nuclear receptors
are soluble proteins found either in the cytoplasm (class I) or
Response (% maximum)

within the cell nucleus (class II). Agonist activation of class I 80

targets (e.g. by steroids or prolactin) results in the formation of

dimeric receptor complexes, which translocate into the nucleus
Efficacy

60
and bind to hormone-response elements within DNA to regulate
gene transcription. Class II receptors reside within the cell nu-
a b
cleus and regulate lipid and drug metabolizing enzymes. Both 40
classes of receptor contain highly conserved structural motifs c
(zinc fingers) to assist with recognition and binding of the re-
Decreasing

ceptor to hormone response elements of DNA. 20

Agonists
0
An agonist is a chemical that binds to and activates a receptor to 0.01 0.1 1 10 100 1000
alter the function of its host cell. Agonists possess both affinity Log agonist concentration
and efficacy. In simple terms, the ability of an agonist (or drug)
to bind to the receptor is termed affinity and is defined as the Agonists: a and b are full agonists; a is a more potent agonist than b,
but has equal efficacy; c has a lower efficacy (partial agonist) than
ratio of the binding rate (k 1) and dissociation rate (k  1), that either a or b; a and c are equipotent; c is more potent than b
is, affinity (kA) k 1/k  1, and is often measured experi-
mentally using radioactive binding techniques. In contrast,
Figure 5

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 PHARMACOLOGY

eresponse curve (Figure 6). In contrast, irreversible competitive

Competitive reversible and irreversible antagonists covalently bind to the receptor, and receptor
receptor antagonism blockade cannot be overcome by increasing the agonist con-
100 centration (i.e. the effect is insurmountable). Consequently, the
maximal effect of the agonist is reduced in the presence of irre-
versible antagonist (Figure 6). The only exception to this rule
occurs if there is receptor reserve (i.e. where a limited number of
80 Agonist
Agonist receptors are required for maximal efficacy). In the presence of
Response (% maximum)

alone
+ low concentrations of irreversible antagonist the remaining re-
irreversible
ceptors will produce a full agonist response. However, if the
competitive
60
antagonist concentration of antagonist is increased, receptor reserve is used
up and the maximal response will reduce (i.e. it becomes
insurmountable). Clinically useful examples of irreversible
40
competitive antagonists include aspirin and omeprazole. The
Agonist term non-competitive antagonism is reserved for drugs that do
+
reversible
not compete at the agonist-binding site, but prevent signal
competitive transduction within the receptor complex. The effects of non-
20
antagonist competitive antagonists are also insurmountable.

Inverse agonists
0
Inverse agonists, as their name suggests, produce the opposite
0.01 0.1 1 10 100 1000
effects of agonists. This newly recognized phenomenon
Log agonist concentration is possible only if the receptor is active in the absence of agonist
The binding of a reversible competitive antagonist can be overcome by (i.e. it has constitutive activity). In this situation a competitive
increasing agonist concentration (agonist curve shifts to the right but antagonist on its own will have no effect on constitutive activity
efficacy remains unchanged) whereas an irreversible (or non-competitive)
antagonist decreases the efficacy of the agonist (because no agonist is present), but an inverse agonist will
produce a concentration-dependent reduction in receptor activity
Figure 6 (i.e. it has negative efficacy). Examples of receptors displaying
constitutive activity include certain subtypes of GPCRs, GABA-
ergic and cannabinoid receptors. A
k1
B R # BR#AR/No Effect
k1
FURTHER READING
where: B is the antagonist, R is the receptor, BR is the bound
Alexander SPH, Mathie A, Peters JA. Guide to receptors and channels
receptor.
(GRAC). Brit J Pharmacol 2009; 158: S1e254.
Reversible competitive antagonism is surmountable. In other
Franks NP. Molecular targets underlying general anaesthesia. Br J
words, when an antagonist binds to the agonist binding site its
Pharmacol 2006; 147: S72e81.
effects can be overcome by increasing the concentration of
Rang HP, Ritter JM, Flower RJ, Henderson G. Pharmacology. 8th edn.
competing agonist (e.g. atracurium-induced neuromuscular
Edinburgh: Elsevier/Churchill Livingstone, 2016.
blockade can be overcome by increasing acetylcholine concen-
Weir CJ. The molecular mechanisms of general anaesthesia: dis-
trations with neostigmine, although clinically this is probably
secting the GABAA receptor. Cont Educ Anaesthesia Crit Care Pain
achieved by activating spare receptors). Graphically, this is rep-
2006; 6: 49e53.
resented by a parallel and rightward shift of the concentration

ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 7 2016 Published by Elsevier Ltd.

Please cite this article in press as: Weir CJ, Ion channels, receptors, agonists and antagonists, Anaesthesia and intensive care medicine (2016),
http://dx.doi.org/10.1016/j.mpaic.2016.09.016