Drug receptor interactions in anaesthesia

Question 1

Key points

Answer 1

There are four main classes of receptors:
(i) Gprotein- coupled receptors;
(ii) ligand-gated ion channels;
(iii) intracellular receptors; and
(iv) tyrosine kinase-coupled receptors.

Drug-receptor interactions are characterised by affinity, potency and efficacy.

Drugs with different efficacies (full agonist, partial
agonist, antagonist) offer broad treatment
options.

Using opioids as exemplars, drugs that target multiple
members of the receptor family or show bias
towards different parts of the signalling pathway
have potential advantages in terms of their analgesic
effects.

Question 2

Drug targets

Answer 2

Enzymes such as cyclooxygenase on which NSAIDS act to
produce analgesia and anti-inflammatory actions,
phosphodiesterases (PDEs) on which inhibitors such as
sildenafil and tadalafil act to treat erectile dysfunction
(PDE-5 inhibitors), and acetylcholinesterase on which
neostigmine acts to reverse neuromuscular block.

Ion channels such as voltage-gated Ca2þ channels that are
blocked by calcium channel blockers such as amlodipine

Cell membrane carrier proteins, for example monoamine
reuptake transporters where inhibition increases the
concentration of one, or more, of three major monoamine
neurotransmitters: serotonin (5-hydroxytryptamine),
noradrenaline (norepinephrine) and dopamine

Receptors, which will be the focus of the remainder of this
article.

Question 3

Receptors

Answer 3

Receptors are target proteins responding to the binding of
chemical messenger(s) to modify a cellular response. They are
able to respond to various messengers and facilitate complex
and coordinated communications within the body. These
various messengers include neurotransmitters, hormones,
chemokines and exogenous therapeutic drugs. Receptors can
be targeted by drugs, which either mimic or antagonise
endogenous mediators.

Question 4

G-protein coupled receptors

Answer 4

All GPCRs have a common structure; an extracellular N terminus,
an intracellular C terminus and seven transmembrane
domains joined by intracellular and extracellular loops. The
binding of a ligand to a GPCR results in structural changes to the
receptor that enable it to interact with the intracellular G-protein,
which is formed of a, b and g subunits. After this interaction
between receptor and G-protein, the G-protein separates
into subunits, a Ga-subunit and bg complex, both of which
interact with second messenger pathways

Question 5

Affinity

Answer 5

terms. A drug’s affinity (strength of binding) for a
given receptor is the product of its association with receptor
together with the rate of dissociation of drugereceptor complex

High affinity drugs only need a low concentration

Question 6

Agonists

Answer 6

Agonists bind to receptors to induce conformational changes
within the receptor and a cascade of functional biological
responses

Question 7

The efficacy

Answer 7

The efficacy of a drug is the response generated per unit drug receptor complex

Question 8

Antagonists

Answer 8

Antagonists have affinity for receptors but no efficacy and
therefore do not activate second messenger pathways.

prevent
agonist action.

competitive such that the
binding is reversible and surmountable, or non-competitive
when the binding is irreversible and insurmountable

when the binding is irreversible and insurmountable.
Naloxone is a competitive opioid antagonist and has high
affinity at MOP receptors

Question 9

Summary

Answer 9

Therapeutic drug interaction is mainly described by
ligandereceptor interactions, although there are high profile
examples of ligandeenzyme interaction in anaesthesia such
as cholinesterase inhibitors

Answer 10

In addition, sugammadex, the
neuromuscular blocking agent reversal drug, reverses
neuromuscular block by encapsulation of rocuronium and
vecuronium.

Question 11

Ligandereceptor interaction

Answer 11

Ligand receptor interaction is defined by
affinity
(strength of interaction), and

the consequences of that
interaction is described by potency (dose range over which the
effect is produced) and efficacy (effectively the size of the response).

Question 12

Agonists

Answer 12

Agonists and antagonists have affinity, but agonists
produce a functional response that can be ‘standard’ or
inverse. Antagonists reverse the effects of agonists in a
competitive or non-competitive (also irreversible) manner,
and there are examples of all classes in drugs used in anaesthesia
and pain medicine.