Inflammation, allergic diseases and immunosuppression

10 Inflammation, allergic diseases and immunosuppression

After reading this chapter, you will:

• Understand the basic principles behind inflammation, allergies and immunosuppression

• Know the different drug classes used to treat these conditions and their mechanism of action

• Be aware of the indications, contraindications and adverse drug reactions.

Inflammation

Inflammation describes the changes seen in response to tissue injury or insult including pain, redness, heat, swelling and loss of function. These changes occur because of dilatation of local blood vessels, which lead to increased permeability and increased receptiveness for leucocytes. This results in the accumulation of inflammatory cells at the site of injury. The main cells seen in an acute inflammatory response are neutrophils and macrophages. Lymphocytes, basophils and eosinophils also accumulate.

Inflammatory responses are produced and controlled by the interaction of a wide range of inflammatory mediators, some derived from leucocytes, some from the damaged tissues. Examples include:

• Kinins (bradykinin)

• Neuropeptides (substance-P, calcitonin gene-related peptide)

• Cytokines (e.g. interleukins (ILs))

• Arachidonic acid metabolites (eicosanoids).

Arachidonic acid metabolites: the eicosanoids

Of the inflammatory mediators mentioned above, the eicosanoids are of special importance because they are involved in the majority of inflammatory reactions and thus most anti-inflammatory therapy is based on the manipulation of their biosynthesis.

The eicosanoids are a family of polyunsaturated fatty acids formed from arachidonic acid. The biosynthetic pathway is shown in Figure 10.1. Arachidonic acid is derived mainly from phospholipids of cell membranes, from which it is mobilized by the action of the enzyme phospholipase A₂. Arachidonic acid is then further metabolized:

• By cyclooxygenase to produce the ‘classic prostaglandins’, thromboxane and prostacyclin, collectively known as the prostanoids

• By lipoxygenase to produce the leukotrienes

Fig. 10.1 Biosynthetic pathway of the eicosanoids. (HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LT, leukotrienes; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin.)

The actions of eicosanoids in inflammatory reactions are listed in Figure 10.2.

Fig. 10.2 Actions of the eicosanoids in the inflammatory reaction

Anti-inflammatory drugs

The main drugs used for their broad-spectrum anti-inflammatory effects are:

• Non-steroidal anti-inflammatory drugs.

• Steroidal anti-inflammatory drugs (glucocorticoids) (Ch. 6 and p. 154).

Both these classes of anti-inflammatory drug exert their effect by inhibiting the formation of eicosanoids (see Fig. 10.1).

In addition, a number of other drug classes have more restricted anti-inflammatory actions. These are:

• Disease-modifying antirheumatic drugs (DMARDs) (p. 155)

• Drugs used to treat gout (p. 156)

• Antihistamines (p. 162)

• Drugs used to treat skin disorders.

NSAIDs

NSAIDs all possess the ability to inhibit both forms of the enzyme cyclooxygenase (see Fig. 10.1), an action that is responsible for their pharmacological effects (see Fig. 10.4).

The first drugs of this type were the salicylates (e.g. aspirin), extracted from the bark of the willow tree. Subsequently, many synthetic and semi-synthetic NSAIDs have been created. Chemically and structurally heterogeneous, they are related through their common mechanism of action (Fig. 10.3).

Fig. 10.3 Classes of non-steroidal anti-inflammatory drugs and comparison of their main actions

Mechanism of action

The main action of all the NSAIDs is inhibition of the enzyme cyclooxygenase. This enzyme is involved in the metabolism of arachidonic acid to form the prostanoids, i.e. the ‘classic prostaglandins’, prostacyclin and thromboxane A₂. Inhibition of cyclooxygenase can occur by several mechanisms:

• Irreversible inhibition – e.g. aspirin causes acetylation of the active site.

• Competitive inhibition – e.g. ibuprofen acts as a competitive substrate.

• Reversible, non-competitive inhibition – e.g. paracetamol has a free radical trapping action that interferes with the production of hydroperoxidases, which are believed to have an essential role in cyclooxygenase activity.

Cyclooxygenase exists in two enzyme isoforms:

• COX-1: Expressed in most tissues, especially platelets, gastric mucosa and renal vasculature, and involved in physiological cell signalling. Most adverse effects of NSAIDs are caused by inhibition of COX-1.

• COX-2: Induced at sites of inflammation and produces the prostanoids involved in inflammatory responses. Analgesic and anti-inflammatory effects of NSAIDs are largely due to inhibition of COX-2.

COX-2-specific inhibitors have a reduced incidence of gastric side-effects. However, they are associated with an increased incidence of adverse cardiovascular events (such as myocardial infarction).

Clinical effects

NSAIDs work by the inhibition of cyclooxygenase and resulting inhibition of prostaglandin synthesis, producing three major clinical actions of potential therapeutic benefit: analgesia, an anti-inflammatory action and an antipyretic action (Fig. 10.4).

Fig. 10.4 Three major clinical actions of non-steroidal anti-inflammatory drugs (NSAIDs)

Not all NSAIDs possess these three actions to exactly the same extent, an example being the lack of anti-inflammatory activity possessed by paracetamol (see Fig. 10.3).

In addition aspirin has a pronounced effect on inhibiting platelet aggregation, due to reduced thromboxane synthesis. It is used in the primary and secondary prevention of cardiovascular and cerebrovascular events (Ch. 2).

Indications

NSAIDs are widely used for a variety of complaints. They are available on prescription and ‘over the counter’. Their use includes musculoskeletal and joint diseases (strains, sprains, rheumatic problems, arthritis, gout, etc.), analgesia for mild to moderate pain relief and symptomatic relief in fever.

Contraindications

NSAIDs should not be given to people with gastrointestinal ulceration or bleeding, or a previous hypersensitivity to any NSAID. Caution should be used in asthma and when renal function is impaired.

Adverse effects

Generalized adverse effects of NSAIDs are common, especially in the elderly and in chronic users, and mostly arise from the non-selective inhibition of COX-1 and COX-2 (Fig. 10.5).

Fig. 10.5 General adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs)

Less commonly, liver disorders and bone marrow depression are seen. Other unwanted effects that are relatively specific to individual compounds are also seen (see below).

Therapeutic notes on individual NSAIDs

Salicylic acids, e.g. aspirin:

• Is cheap, and is still the drug of choice for many sorts of mild pain despite a relatively high incidence of gastrointestinal side-effects. It is also used for its antiplatelet action

• Produces tinnitus in toxic doses.

Propionic acids, e.g. ibuprofen:

• Has a low incidence of side-effects.

Acetic acids, e.g. indometacin:

• Is a highly potent inhibitor of COX that is effective but associated with a high incidence of side-effects.

• May cause neurological effects such as dizziness and confusion, as well as gastrointestinal upsets.

Oxicams, e.g. piroxicam:

• Is a potent drug widely used for chronic inflammatory conditions.

• Is given only once daily, but causes a relatively high incidence of gastrointestinal problems.

Pyrazolones, e.g. phenylbutazone:

• Is an extremely potent agent but can produce a fatal bone marrow aplasia. For this reason it is reserved for the treatment of intractable pain in ankylosing spondylitis.

Fenemates, e.g. mefenamic acid:

• Is a moderately potent drug

• Commonly causes gastrointestinal upsets and occasionally skin rashes.

para-Aminophenols, e.g. paracetamol:

• Is used as an analgesic and antipyretic but is not considered an anti-inflammatory drug.

• Is effective for pain, especially headaches, and fever. This is probably due to its mechanism of action in trapping free radicals and interfering with the production of hydroperoxidases, which are believed to have an essential role in cyclooxygenase activity. In areas of inflammation, phagocytic cells produce high levels of peroxide that swamp this effect. For more information see Chapter 9.

COX-2 specific inhibitors, e.g. lumiracoxib and celecoxib:

• Preferentially inhibit the inducible COX-2 enzyme, limiting COX-1-mediated side-effects observed with other, non-specific NSAIDs.

The COX-2 inhibitors are licensed in the UK for symptomatic relief in osteoarthritis and rheumatoid arthritis. They are contraindicated in inflammatory bowel disease, ischaemic heart disease or cerebrovascular disease.

Steroidal anti-inflammatory drugs (glucocorticoids)

There are two main groups of corticosteroids, the glucocorticoids and the mineralocorticoids. It is the glucocorticoids (such as cortisone and cortisol), which posses powerful anti-inflammatory actions that make them useful in several diseases, e.g. rheumatoid arthritis, inflammatory bowel conditions, bronchial asthma (see Ch. 3) and inflammatory conditions of the skin.

Their profound generalized inhibitory effects on inflammatory responses result from the effects of corticosteroids in altering the activity of certain corticosteroid-responsive genes. The anti-inflammatory action results from:

• Reduced production of acute inflammatory mediators, especially the eicosanoids (see Fig. 10.1). Corticosteroids prevent the formation of arachidonic acid from membrane phospholipids by inducing the synthesis of a polypeptide called lipocortin. Lipocortin inhibits phospholipase A₂, the enzyme normally responsible for mobilizing arachidonic acid from cell membrane phospholipids, and thus inhibits the subsequent formation of both prostaglandins and leukotrienes.

• Reduced numbers and activity of circulating immunocompetent cells, neutrophils and macrophages.

• Decreased activity of macrophages and fibroblasts involved in the chronic stages of inflammation, leading to decreased inflammation and decreased healing. Glucocorticoids are discussed in detail in Ch. 6.

Inflammatory diseases

Rheumatoid arthritis

DMARDs (disease modifying anti-rheumatic drugs)

DMARDs are a diverse group of agents that are mainly used in the treatment of rheumatoid arthritis, which is a chronic, progressive and destructive inflammatory disease of the joints (Fig. 10.6).

Fig. 10.6 Disease-modifying antirheumatic drugs (DMARDs)

The mechanism of action of the DMARDs is often unclear – they appear to have a long-term depressive effect on the inflammatory response as well as possibly modulating other aspects of the immune system.

All DMARDs have a slow onset of action, with clinical improvement not becoming apparent until 4–6 months after the initiation of treatment. DMARDs have been shown to improve symptoms and reduce disease activity. They are believed to slow erosive damage at joints.

DMARDs are generally indicated for use in severe, active, progressive rheumatoid arthritis when NSAIDs alone have proved inadequate. DMARDs are frequently used in combination with an NSAID and/or low-dose glucocorticoids.

Immunosuppressants

Certain drugs with immunosuppressive actions have been shown to be effective in rheumatoid arthritis. These include azathioprine, ciclosporin and corticosteroids which may work by suppressing the autoimmune component of rheumatoid arthritis (p. 154).

DMARDs are prescribed by a specialist. Patients taking these agents need regular blood tests to assess their renal and liver function, and to monitor their red and white blood cell counts.

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Tags: Crash Course Pharmacology

Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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