The term acute inflammatory reaction refers to the local events which occur in response to a disease-causing organism (pathogen). It consists of the innate immune response (non-memory) and may have an immunologically specific reaction superimposed on top (adaptive immune responses, where the host has memory of the pathogen through previous exposure and accelerates the acute inflammatory reaction, see below). These reactions are critical for host defence. However, if they are inappropriately deployed, as occurs in many diseases, they are deleterious. It is, therefore, important to understand the mediators which control these responses since many drugs currently used or in development are directed at influencing the generation and/or action of these mediators.
The innate acute inflammatory reaction involves both vascular events (vasodilatation, increased permeability of the postcapillary venules, exudation of fluid) and cellular events. The cells involved are (1) white blood cells (neutrophils, monocytes, lymphocytes, natural killer lymphocytes), which accumulate in the area of inflammation and are activated, some to ingest microorganisms or kill infected cells and some to release mediators, and (2) tissue cells (vascular endothelial cells, mast cells, macrophages). The mediators derived from cells include eicosanoids, cytokines, histamine, neuropeptides and many others; those derived from plasma include complement components and components of the kinin cascade such as bradykinin.
The adaptive immune response consists of two phases: an induction phase and an effector phase , the latter consisting of an antibody-mediated component and a cell-mediated component. Various cytokines control these phases. The key cells are the lymphocytes of which there are two main types, B cells and T cells. (A third type, natural killer lymphocytes, participates in innate immune responses.) There are several subtypes of T cells ( Fig. 16.1 ). Precursor T cells (ThP) give rise to Th0 cells (not shown in figure), which can be stimulated to develop into helper T cells (Th). The cytokine interleukin-2 (IL-2) drives the differentiation of ThP and Th1 cells ( Fig. 16.1 ). On first exposure to antigen, memory B cells and T cells are produced; these speed up the response when that antigen is encountered again:
Th1 cells activate and participate in the pathway to cell-mediated immunity.
Th2 cells activate the pathway to humoral (antibody-mediated) immunity by stimulating the proliferation of B cells that mature to plasma cells (P) which generate antibodies. (But note that not all B cell responses are dependent on interaction with Th2 cells.)
Immune responses, meant for defence, can themselves cause damage if inappropriately triggered. Many diseases are caused by, or have a component of, inappropriately induced immune/inflammatory reactions. Some are associated with Th1 responses (e.g. rheumatoid arthritis, multiple sclerosis, aplastic anaemia, insulin-dependent diabetes), and the Th1 pathway is also involved in allograft rejection. Inappropriate Th2 responses are implicated in various allergic (hypersensitivity) conditions. The term autoimmune disease is applied to conditions in which the immune response is directed against the body’s own tissues. Conversely, some cancers are now being treated with drugs ( immunostimulants ) that boost the adaptive immune response to lead to better cancer cell killing.
The eventual outcome of inflammation can be resolution and healing (possibly with scarring) or – if the pathogen or eliciting agent persists – the development of a chronic inflammatory reaction .
Mediators of Inflammation and the Drugs Affecting Them
Eicosanoids and platelet-activating factor
Eicosanoids (prostanoids, leukotrienes) and platelet-activating factor are generated from phospholipids and are implicated in many physiological and pathological processes. Many drugs target steps in their production ( Fig. 16.2 ). An important enzyme is cyclooxygenase (COX), which occurs in two main forms: COX-1 (a constitutive enzyme expressed in most cells and involved in tissue homeostasis) and COX-2 (which is induced in activated inflammatory cells). A COX-3 enzyme has also been described.
Bradykinin is a nonapeptide clipped out of a plasma α-globulin. Its actions in inflammation are:
vasodilatation (mediated by released nitric oxide (NO) and prostaglandin I 2 (PGI 2 ),
increased vascular permeability, and
stimulation of pain nerve endings (this is potentiated by prostaglandin (PGs)).
Histamine is released from mast cells by a complement component C3a or, in type I hypersensitivity, by an antigen–antibody reaction on the cell surface.
Most inflammatory cells express the inducible form of NO synthase when activated by cytokines. NO dilates blood vessels, increases vascular permeability and stimulates PG release.
Cytokines are a large family of peptide mediators that are released or generated in inflammatory and immune reactions and which control the actions of inflammatory and immune cells by autocrine or paracrine mechanisms. They include interleukins (IL) (some of relevance to drugs include IL-2, tumour necrosis factor α (TNF-α) and IL-5), chemokines (mediators that attract and activate motile inflammatory cells such as polymorphs and macrophages), colony-stimulating factors (e.g. G-CSF), growth factors (VEGF, TGFβ) and many others.
The principal anti-inflammatory agents are:
the glucocorticoids, and
the nonsteroidal anti-inflammatory drugs (NSAIDs).
Others that are disease specific are:
antirheumatoid drugs, and
drugs used in the treatment of gout.
Nonsteroidal Anti-Inflammatory Drugs
The degree to which NSAIDs inhibit the two COX enzymes varies as follows:
Highly COX-1-selective : ketorolac; very COX-1-selective : flurbiprofen; weakly COX-1-selective : indometacin, ibuprofen, aspirin, naproxen, paracetamol. Paracetamol may also inhibit COX-3 in the central nervous system (CNS).
Very COX-2-selective : etoricoxib; weakly COX-2-selective : piroxicam, diclofenac, celecoxib. (Note that agents that are weakly COX-2 selective also inhibit COX-1.)
NSAIDs reduce those aspects of inflammation in which the COX-2 products have a role, specifically vasodilatation, which in turn facilitates increased permeability of the postcapillary venules. Some are strongly anti-inflammatory (e.g. naproxen, piroxicam, celecoxib), and some moderately so (e.g. ibuprofen). Some have little anti-inflammatory effect (e.g. paracetamol).
NSAIDs reduce pain caused by tissue damage or by inflammatory mediators that act on nerve endings (bradykinin, 5-hydroxytryptamine; see Chapter 13 ). The action is indirect in that the NSAIDs decrease the production of PGs, which sensitize the nerve endings to these pain-producing mediators.
NSAIDs reduce fever. Body temperature is controlled by a hypothalamic ‘thermostat’ which ensures that heat production and heat loss are in balance around a set-point. Fever occurs when IL-1, an inflammatory mediator, generates, in the hypothalamus, E-type PGs that disturb the hypothalamic thermostat, elevating the set-point. NSAIDs act by interrupting the synthesis of the relevant PGs.
Mechanism of action
All NSAIDs act mainly by inhibiting COX enzymes (see above). With most agents, the effect is reversible; the exception is aspirin which causes irreversible inactivation of the enzymes.
NSAIDs are usually given orally. Naproxen and indometacin can be given by rectal suppository, piroxicam by intramuscular (IM) injection or suppository, diclofenac by IM, intravenously or rectal suppository. Some have a short half-life of 1–4 h (aspirin, paracetamol ibuprofen); some have a rather longer half-life (e.g. naproxen 14 h, celecoxib 11 h); some have a very long half-life (piroxicam 45 h). Note that aspirin’s action lasts longer because it acetylates the COX enzymes.
Adverse effects (largely due to COX-1 actions) are frequently reported, particularly if large doses are taken over a long period.
Gastrointestinal (GI) disturbances are the most common. Locally produced PGs inhibit acid secretion in the stomach, have a cytoprotective effect by stimulating mucus and bicarbonate secretion and cause vasodilatation. NSAIDs decrease the synthesis of PGs and thus can cause mucosal damage and bleeding. The risk is greatest with piroxicam, less with naproxen and diclofenac, less still with ibuprofen and least with the COX-2 inhibitors. Misoprostol , a synthetic PG receptor agonist, can prevent NSAID-induced mucosal damage in patients with a peptic ulcer who need to take non-selective NSAIDs.
Skin reactions are fairly common, particularly with sulindac.
Adverse renal effects occur because NSAIDs decrease local renal PG levels. These PGs increase blood flow and promote natriuresis. NSAIDs can produce reversible renal insufficiency by decreasing PG-induced compensatory vasodilatation, an effect more serious in conditions such as liver disease or heart failure. Long-continued NSAID consumption can result in significant renal damage: chronic nephritis and papillary necrosis.
Bone marrow depression and liver disorders are less frequent. Toxic doses of paracetamol, sometimes taken in suicide attempts, can cause potentially fatal liver damage.
A particular type of encephalitis (Reye’s syndrome) can be precipitated by aspirin in children with viral infections. Aspirin may cause bronchospasm in susceptible individuals and NSAIDs in general are contraindicated in asthma.
The possibility of adverse cardiovascular effects with COX-2 selective NSAIDs especially requires caution.