Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

DRUG RECEPTORS
antibiotics are poorly absorbed if given by mouth,
e.g. neomycin; thus they will have a selective effect
on gut bacteria. However, if neomycin is administered
parenterally it will gain access to bacterial
infections in other tissues, as well as potentially
causing systemic toxicity. Intra-articular administration
of corticosteroids reduces the systemic effects of
the drug while achieving a local effect.
Increasingly, as more is understood about the nature of
receptors, it is clear that there are different subtypes of
receptor within a given class, each mediating a different
response. For example, there are a number of different
dopamine receptors, some confined to the central
nervous system, others to the cardiovascular system.
While dopamine may be the endogenous agonist,
through selective structural modifications, drugs have
been synthesized that act selectively either as agonists
or antagonists at each of the receptor subtypes. A similar
approach has been applied to histaminergic, opioid and
serotonergic drugs. GABA receptors have several subunits
(α, β and γ). GABA receptors throughout the CNS
are composed of different combinations of subunits,
which affects their function and interaction with different
drugs. It is important to recognize the complexity of
physiological pathways and their interactions and interdependence.
Specificity of drug–receptor interactions
may be evident at the molecular level, but loss of apparent
specificity of action may be evident as effects at the
cellular, tissue and whole organism level are investigated
and homeostatic compensatory processes are
recruited.
Receptor occupancy
In the classic theory of receptor occupancy, drug effect
is proportional to the number of receptors occupied by
drug. Maximal effect occurs when all receptors are
occupied. There are, however, many exceptions to this
where maximal effect can be achieved when only a critical
proportion of receptors is occupied, indicating that
spare receptors exist.
Other receptors may have multiple drug binding sites
(allosteric sites), which may not act independently. Drug
attachment at one point may alter the characteristics of
agonist– or antagonist–receptor interactions at other
locations.
Regulation of receptors
Receptor density and sometimes affinity for agonists
and antagonists are dynamic and often influenced by
receptor–drug interactions.
● Downregulation. Continual stimulation of cells by
an agonist may result in a state of desensitization,
whereby the concentration of agonist required to
produce a certain effect is increased. This may occur,
for example, with benzodiazepine therapy. Downregulation
of myocardial β-receptors occurs in
cardiac failure as a result of increased sympathetic
stimulation.
● Upregulation. Additional receptors can be synthesized
in response to chronic receptor antagonism.
When the cell is subsequently exposed to the agonist,
more receptors are available, causing a hyperreactive
response or supersensitivity.
Signaling mechanisms and drug action
When a drug binds to a receptor it initiates a sequence
of events that culminates in the drug effect. How does
the message get from a membrane-bound receptor to the
site of action within the cell? Several mechanisms have
been identified.
● Induction of synthesis of specific proteins by intracellular
receptors that regulate gene expression. For
example, lipid-soluble hormones such as corticosteroids,
sex steroids, vitamin D and thyroid hormones
are sufficiently lipid soluble to cross plasma membranes.
Interactions with intracellular receptors
(notably members of the superfamily of nuclear
receptors) stimulate transcription of genes by binding
to specific DNA sequences. In some cases (e.g. glucocorticoids),
once the hormone has bound to the
receptor in the cytoplasm, the receptor–ligand
complex moves to the nucleus. In other cases (e.g.
estrogen and thyroid hormone), the receptor is principally
located in the nucleus. As a result of this
mechanism these hormones produce their effects
after a lag period (30 min to several hours) as their
effects depend on regulation of gene expression and
protein synthesis. The effects of these agents can
persist for hours or days after the agonist concentration
has been reduced below the level of detection
because new enzymes and proteins that have been
synthesized remain active until degraded by normal
mechanisms.
● Regulation of gated ion channels in the plasma membrane.
Drugs may mimic or block actions of endogenous
ligands that regulate the flow of ions through
transmembrane ion channels. Natural ligands include
glutamate, γ-amino butyric acid (GABA) and acetylcholine.
For example, barbiturates and benzodiazepines
influence chloride ion channel function;
local anesthetic agents influence sodium channel
function.
● Regulation of plasma membrane enzymes. Numerous
receptors activate or inhibit plasma membrane
enzymes. The primary enzyme affected is adenyl
cyclase, which is the enzyme responsible for intracel-
7