DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

IL-1 comprises two distinct polypeptides (IL-1α and IL-1β)
that bind to an 80-kd IL-1 receptor type 1 and a 68-kd IL-1 receptor
type 2, which are present on different cell types (O’Neill, 2008).
Plasma IL-1 levels are increased in patients with active inflammation.
A naturally occurring IL-1 receptor antagonist (IL-1ra) competes
with IL-1 for receptor binding and blocks IL-1 activity in vitro
and in vivo. IL-1ra often is found in high levels in patients with various
infections or inflammatory conditions and may act to limit the
extent of an inflammatory response. Clinical studies suggest that the
administration of a recombinant form of human IL-1ra (anakinra;
see Chapter 35) antagonizes IL-1 action at its receptor and thereby
inhibits the progression of structural damage associated with active
rheumatoid arthritis and other inflammatory conditions.
Canakinumab (ILARIS) is an IL-1β monoclonal antibody recently
approved for two forms of the cryopyrin-associated periodic syndrome:
familial cold auto-inflammatory syndrome and Muckle-
Wells syndrome (see Chapter 35).
Other cytokines and growth factors (e.g., IL-2,
IL-6, IL-8, GM-CSF) contribute to manifestations of
the inflammatory response. The concentrations of many
of these factors are increased in the synovia of patients
with inflammatory arthritis. Glucocorticoids interfere
with the synthesis and actions of cytokines, such as IL-1
or TNF-α (see Chapter 35). Although some of the
actions of these cytokines are accompanied by the
release of PGs and thromboxane A 2
(TxA 2
), COX
inhibitors appear to block only their pyrogenic effects.
In addition, many of the actions of the PGs are
inhibitory to the immune response, including suppression
of the function of helper T cells and B cells and
inhibition of the production of IL-1 (see Chapter 33).
Other cytokines and growth factors counter the effects
and initiate resolution of inflammation. These include
transforming growth factor β 1
(TGF-β 1
), which
increases extracellular matrix formation and acts as an
immunosuppressant; IL-10, which decreases cytokine
and PGE 2
formation by inhibiting monocytes; and
interferon gamma (IFN-γ), which possesses myelosuppressive
activity and inhibits collagen synthesis and collagenase
production by macrophages.
Many cytokines, including IL-1 and TNF-α, have been found
in the rheumatoid synovium. Rheumatoid arthritis appears to be an
autoimmune disease driven largely by activated T cells, giving rise to
T cell–derived cytokines, such as IL-1 and TNF-α. Activation of B cells
and the humoral response also are evident, although most of the antibodies
generated are immunoglobulins G of unknown specificity,
apparently elicited by polyclonal activation of B cells rather than from
a response to a specific antigen (Brennan and McInnes, 2008).
Pain. Nociceptors, peripheral terminals of primary afferent
fibers that sense pain, can be activated by various
stimuli, such as heat, acids, or pressure. Inflammatory
mediators released from non-neuronal cells during tissue
injury increase the sensitivity of nociceptors and potentiate
pain perception. Some of the main components of
this inflammatory “mélange” are bradykinin, H + , neurotransmitters
such as serotonin and ATP, neutrophins
(nerve growth factor), LTs, and PGs. Cytokines appear to
liberate PGs and some of the other mediators.
Neuropeptides, such as substance P and calcitonin generelated
peptide (CGRP), also may be involved in eliciting
pain (see Chapter 18).
PGE 2
and PGI 2
reduce the threshold to stimulation
of nociceptors, causing peripheral sensitization
(Lopshire and Nicol, 1998; Pulichino et al., 2006).
Thus, PGE 2
promotes—probably via its receptors, EP 1
and EP 4
—the phosphorylation of transient receptor
potential V 1
and other ion channels on nociceptors and
increases their terminal membrane excitability.
Reversal of peripheral sensitization is thought to represent
the mechanistic basis for the peripheral component
of the analgesic activity of NSAIDs. NSAIDs also have
important central actions in the spinal cord and brain.
Both COX-1 and COX-2 are expressed in the spinal
chord under basal conditions and release PGs in
response to peripheral pain stimuli (Vanegas and
Schaible, 2001). Centrally active PGE 2
and perhaps
also PGD 2
, PGI 2
, and PGF 2α
contribute to central sensitization,
an increase in excitability of spinal dorsal
horn neurons that causes hyperalgesia and allodynia in
part by disinhibition of glycinergic pathways (Reinold
et al., 2005).
Basal COX-2, expressed in both neurons and glia cells, contributes
to central sensitization in the early phase of peripheral
inflammation. COX-2 is upregulated widely in the spinal chord
within a few hours to contribute to prolonged central sensitization
(Samad et al., 2001). A role for COX-1 in nociception has been
implicated by COX-1–deleted mice, which show increased tolerance
to pain stimuli (Ballou et al., 2000). This isoform is predominant in
neurons of dorsal root ganglia. Central sensitization reflects the plasticity
of the nociceptive system that is invoked by injury. This usually
is reversible within hours to days following adequate responses
of the nociceptive system (e.g., in postoperative pain). However,
chronic inflammatory diseases may cause persistent modification of
the architecture of the nociceptive system, which may lead to longlasting
changes in its responsiveness. These mechanisms contribute
to chronic pain.
Fever. Regulation of body temperature requires a delicate
balance between the production and loss of heat; the
hypothalamus regulates the set point at which body temperature
is maintained. This set point is elevated in fever,
reflecting an infection, or resulting from tissue damage,
inflammation, graft rejection, or malignancy. These
conditions all enhance formation of cytokines such as
IL-1β, IL-6, TNF-α, and interferons, which act as
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CHAPTER 34
ANTI-INFLAMMATORY, ANTIPYRETIC, AND ANALGESIC AGENTS; PHARMACOTHERAPY OF GOUT