Drugs used in inflammation

Different types of arthritis (rheumatic disease) are treated with different drugs. The aim of the clinician is to prescribe drugs which improve symptoms and, where possible, slow or halt progress of the condition. As their name suggests, disease-modifying anti-rheumatic drugs (DMARDs) offer benefit via the latter mechanism. Full therapeutic response to DMARDs may take several months to become evident. Early intervention with DMARD therapy is recommended to control the signs and symptoms of rheumatic disease and to limit joint damage.

There are two main categories: conventional DMARDs and biological therapies. This topic covers conventional DMARDs, biological therapies are described in the Biological DMARDs topic.

Conventional DMARDs include:

Methotrexate is an oral medication prescribed for moderate to severe RA.

Gold (as sodium aurothiomalate) is given by deep intramuscular injection for active progressive RA. This is a long-term treatment, requiring regular dosing up to 5 years post-complete remission. Second courses of gold are not usually effective if the patients suffers a complete relapse.

Penicillamine has a similar action to gold. Penicillamine should be discontinued if there is no improvement within 1 year.

Sulfasalazine is prescribed for active RA on expert advice.

Hydroxychloroquine is prescribed for active RA on expert advice. 

Because of their toxicity, these next immunosuppressants are only used for RA when patients have not responded to other DMARDs:

Ciclosporin, a calcineurin inhibitor: only prescribed for severe active RA when conventional second-line therapy is inappropriate or ineffective.

Leflunomide is a pyrimidine synthesis inhibitor which regulates autoimmune lymphocytes. Used by specialist practitioners for treating moderate to   severe active RA and active psoriatic arthritis.

Cyclophosphamide can be prescribed for RA with severe systemic manifestations and other connective tissue diseases (e.g. active vasculitis).

Azathioprine can be prescribed for RA that has not responded to other DMARDS.

Prescribers should consider co-morbidity and patient preference when choosing which DMARD (or combination of DMARDs) to prescribe. Whilst providing similar efficacy as intramuscular gold and penicillamine, methotrexate or sulfasalazine are often better tolerated. Gold and penicillamine can be effective in palindromic rheumatism. Methotrexate is generally prescribed alongside at least one other DMARD, and often short-term corticosteroid treatment for newly diagnosed RA.

Tofacitinib is an immunomodulating agent and DMARD with a novel mechanism of action. It selectively inhibits the activity of Janus kinase 3 (JAK3), a hematopoietic cell-restricted mediator of cytokine, growth factor, and interferon signalling via the JAK-STAT pathway. Inhibition of JAK3 appears to disrupt development and function of T, B, and NK cells. The FDA has approved tofacitinib for use in the management of moderate to severe active RA in patients who have shown an inadequate response or intolerance to methotrexate. Tofacitinib can be used alone or in combination with methotrexate or other nonbiologic DMARDs, although concomitant use with biologic DMARDs (e.g. adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, anakinra or rituximab), selective costimulation modulators (abatacept), and the anti-interleukin-6-receptor monoclonal antibody tocilizumab, is not recommended. Concomitant use with other immunosuppressive agents  (e.g. azathioprine or cyclosporine) is also not recommended. Serious, sometimes fatal infections (including cryptococcosis, pneumocystosis, tuberculosis and other mycobacterial infections, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infection) have been reported. Tofacitinib treatment should not be initiated in patients with active infections.

The antihistamines recommended for or prescribed to treat allergic reactions, occasional insomnia, motion sickness or vertigo, and nausea and vomiting target histamine H₁ receptors on mast cells, smooth muscle, endothelium, and in the brain’s tuberomammillary nucleus (a structure of histamine-releasing neurons in the posterior third of the hypothalamus involved in regulating arousal, learning, memory, sleep and energy balance). Antihistamine drugs act mechanistically as receptor antagonists or inverse agonists. The only clinically used inverse agonists are cetirizine, desloratadine and pyrilamine (a.k.a. mepyramine maleate- available OTC in British pharmacies). All first-generation antihistamines cause sedation: alimemazine tartrate and promethazine are highly sedating compared to chlorphenamine maleate and cyclizine which are less sedating. Newer second- or third-generation antihistamines with reduced ability to cross the blood brain barrier are classified as ‘non-sedating’.

All antihistamines have potential efficacy for reducing rhinorrhoea and sneezing associated with allergic rhinoconjunctivitis, and may be of some use in treating vasomotor rhinitis. Topically applied antihistamines are used in the eye, nose and on the skin. Oral antihistamines are effective in preventing urticaria, being used to treat urticarial rashes, pruritus, and insect bites/stings. Antihistamines are also used to manage drug allergies, and chlorphenamine maleate or promethazine hydrochloride injections are used along with adrenaline in emergency medicine to treat anaphylaxis and angioedema.

Some antihistamines are porphyrinogenic, so should be avoided in patients with acute porphyrias: alimemazine, chlorphenamine, desloratadine, fexofenadine, ketotifen, loratadine, and promethazine are considered to be safe in these patients.

Non-immune uses of H₁ antihistamines (e.g. anti-emetic, and anti-insomnia use) and H₂ receptor antagonists are discussed elsewhere.

The majority of antihistamines are available from a pharmacy without prescription. Some common examples are highlighted in the following sections.

Sedating antihistamines: the sedating effect of this group of antihistamines can be beneficial for patients whose sleep is disturbed by their symptoms.

Alimemazine tartrate is given orally to treat urticaria and pruritus.

Chlorphenamine maleate can be given to children >1 year old at recommended doses. It is used to provide symptomatic relief from allergies, including hay fever, urticaria, food allergy and drug reactions, as well as from the itch associated with chickenpox. Also used i.m. or i.v. in the emergency treatment of anaphylactic reactions.

Clemastine provides symptomatic relief from allergy. Note that it exhibits significant antimuscarinic activity.

Promethazine teoclate/hydrochloride: the teoclate salt acts longer than the hydrochloride and is used for motion sickness treatment and prevention, nausea, vomiting and labyrinthine disorders. The shorter-acting hydrochloride is used to treat both the symptoms and insomnia associated with urticaria and pruritus, allergy (hay fever and urticaria), emergency treatment of anaphylactic reactions, nausea, vomiting, vertigo, labyrinthine disorders and motion sickness.

Non-sedating antihistamines

Acrivastine provides symptomatic relief of allergy (e.g. hayfever) and chronic idiopathic urticaria. See PubChem CID 5284514 for chemical structure.

Cetirizine hydrochloride & its (R) enantiomer levocetirizine hydrochloride are are both licensed to provide symptomatic relief of allergy such as hay fever and urticaria. Cetirizine is further licensed for chronic idiopathic urticaria and atopic dermatitis. Chemically these are substituted analogues of cyclizine.

Loratadine & its (S) enantiomer desloratadine are licensed to provide symptomatic relief of allergy such as hay fever, chronic idiopathic urticaria. Desloratadine may be marginally superior in managing allergic rhinitis .

Other antihistamines    

Cyclizine is used extensively to treat nausea and vomiting associated with vestibular disorders and palliative care, vertigo and motion sickness. In addition to histamine receptor antagonist activity, cyclizine has significant central anticholinergic(antimuscarinic) activity which likely contributes to its anti-nausea effect.

Emedastine is found in opthalmic solutions used to provide relief from the symptoms of seasonal allergic conjunctivitis.

Epinastine hydrochloride is found in opthalmic solutions used to provide relief from the symptoms of seasonal allergic conjunctivitis.

Olopatadine hydrochloride is found eye drops used to relieve ocular inflammation associated with hay fever. 

The anti-inflammatory corticosteroids act as glucocorticoid receptor agonists and modulate expression of genes containing the glucocorticoid response element (GRE). Although complex, the response appears to include inhibition of the biosynthesis of pro-inflammatory prostaglandins including prostaglandin E2 (PGE₂) and PGI₂ (prostacyclin), and leukotrienes (especially leukotriene LTB₄).

Note: corticosteroid absorption can occur following topical and local use, so be aware of systemic effects if high doses are used or if treatment is prolonged. Potent or very potent topical corticosteroids should be used under specialist supervision in psoriasis.

Examples in clinical use include:

Beclometasone (prodrug beclometasone dipropionate) is prescribed for prophylaxis of asthma (inhalation), allergic and vasomotor rhinitis and severe inflammatory skin disorders such as eczemas unresponsive to less potent corticosteroids (topical), psoriasis (topical) and as an adjunct to aminosalicylates in acute mild to moderate ulcerative colitis (oral).

Betamethasone provides local treatment of inflammation (short term use in eye drops and ointments, intranasal for inflammatory conditions of the nose, ear drops for eczematous inflammation in otitis externa) and for severe inflammatory skin disorders such as eczemas unresponsive to less potent corticosteroids (topical), psoriasis (topical), suppression of inflammatory and allergic disorders (oral).            

Budesonide is delivered by inhalation as prophylaxis and management for mild to moderate asthma. Intranasal delivery is used to manage allergic and vasomotor rhinitis and nasal polyps.

Deflazacort is an oral therapy for suppression of inflammatory and allergic disorders.     

Dexamethasone is administered orally for suppression of inflammatory and allergic disorders, topically for short-term treatment of ocular inflammation, and as intra-articular injection for local inflammation of joints.

Flumetasone contained in ear drops with clioquinol (antifungal/antiprotozoal drug) is used to manage eczematous inflammation in otitis externa and mild bacterial or fungal infections in otitis externa.

Fluorometholone ophthalmic solutions are prescribed for short term local treatment of ocular inflammation.

Fluticasone is applied topically for severe inflammatory skin conditions (dermatitis, eczema, psoriasis), or by inhalation/intranasal administration for prophylaxis of asthma. 

Hydrocortisone (cortisol). In addition to being used as hormone replacement in adrenocortical insufficiency, hydrocortisone is also used to treat mild eczema (topical), severe/life-threatening acute asthma (i.v.) and acute hypersensitivity reactions and anaphylaxis (given i.v. as an adjunct to adrenaline).

Methylprednisolone is prescribed for suppression of inflammatory and allergic disorders (oral), local inflammation in joints and soft tissues (intra-articular injection) and treatment of graft rejection reactions (i.v.).

Loteprednol is prescribed to manage post-operative ocular inflammation.

Mometasone is prescribed as prophylaxis of (severe) asthma (inhalation), treatment of severe inflammatory skin disorders such as eczemas unresponsive to less potent corticosteroids and psoriasis (topical), as well as prophylaxis and treatment of allergic rhinitis (intranasal).

Triamcinolone by intra- or peri-articular administration is used as treatment of local inflammation of joints and soft-tissues (triamcinolone hexacetonide), deep intramuscular injection for suppression of inflammatory and allergic disorders and intranasal administration for prophylaxis and treatment of allergic rhinitis.

Prednisolone is administered orally for mild to moderate acute asthma or severe or life-threatening acute asthma, severe croup, acute exacerbation of chronic obstructive pulmonary disease and for suppression of inflammatory and allergic disorders (including ulcerative colitis, Crohn’s disease and eczematous inflammation in otitis externa (applied locally to the ear)). Can be used short-term to alleviate ocular inflammation.      

Rimexolone is administered for postoperative ocular inflammation and uveitis.

Aminosalicylates (5-aminosalicylate or 5-ASA drugs)

The anti-inflammatory action of these drugs is effective for inducing and maintaining remission in mild to moderate ulcerative colitis and other forms of inflammatory bowel disease and some forms of arthritis (e.g. rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and juvenile idiopathic arthritis). They appear to work (at least in part) by inhibiting the production of pro-inflammatory mediators including prostaglandin, leukotriene, thromboxane and interleukin-1, thereby reducing the acute inflammatory response.

Sulfasalazine for treatment and maintenance of remission of acute mild/moderate and severe ulcerative colitis, active Crohn's disease and sometimes prescribed by clinical specialists for active rheumatoid arthritis. Sulfasalazine’s side-effects are largely caused by the sulfapyridine component of the molecule, so newer 5-ASA only drugs have been developed. These are not effective for rheumatoid arthritis, where the beneficial effects reside with the sulfapyridine component.

5-ASA only drug formulations are equally efficacious and safety is comparable.  The prescriber’s choice of oral 5-ASA drug will be driven by several factors including the indication (e.g. induction or maintenance of remission in ulcerative colitis), disease location, the patient’s preference and their ability to comply with the required dosing regimen, and availability of the drug.

Mesalazine is unconjugated 5-ASA, delivered orally for treatment and maintenance of remission in mild to moderate ulcerative colitis. Available in delayed- and controlled-release formulations which resist gastric breakdown, delivering the drug more effectively to the gut.

Balsalazide (PubChem CID 6335412) consists of one 5-ASA molecule linked to an inert unabsorbed carrier molecule. It is administered orally two to three times a day depending on which formulation is prescribed. Prescribed for treating acute attacks of mild/moderate ulcerative colitis, and maintenance of remission of ulcerative colitis.

Olsalazine (PubChem CID 6003770) is a dimerised 5-ASA prodrug administered orally twice daily for treatment and maintenance of remission of acute mild ulcerative colitis.

Leukotriene receptor antagonists (LTRAs) block the action of leukotriene D4 (and to a lesser extent leukotrienes C₄ and E₄) on the cysteinyl leukotriene receptor CysLT₁ in the lungs and bronchial tubes. This action reduces the inflammatory bronchoconstriction caused by leukotriene. LTRAs are not suitable for treating acute asthma attacks. They do not interact with theophyllines, as they operate by different molecular mechanisms.

Zafirlukast, tablets are prescribed for prophylaxis of asthma, suitable for adults and children. Zafirlukast is often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. Tablets are taken on an empty stomach (one hour before, or two hours after food). Avoidance advised in patients with hepatic impairment, and moderate to severe renal impairment. Common side-effects include gastrointestinal disturbances, headache and respiratory infections.

Montelukast, orally administered drugs are prescribed for prophylaxis of asthma and to provide symptomatic relief of seasonal allergic rhinitis in asthmatic patients. Montelukast is primarily used as a complementary therapy in adults in addition to inhaled corticosteroids, if these are insufficient in controlling their asthma. In addition to film-coated tablets, montelukast is available in chewable tablets and granules that can be mixed in to cold soft food for administration. Like zafirlukast, these medications should be taken on an empty stomach. Common side-effects include gastrointestinal disturbances, headaches, hypersensitivity reactions and drowsiness. The original trade name (under patent coverage) was Singulair, but since patent expiry generic montelukast is sold under a range of brand names.

A drug acting on the same inflammatory pathway is zileuton, which inhibits the 5-LOX (5-lipoxygenase) enzyme that catalyses the formation of leukotrienes LTB₄, LTC₄, LTD₄, and LTE₄ from arachidonic acid. Although not approved for use in the UK, zileuton is approved in the US for the maintenance treatment of asthma. Common side-effects include headache and gastrointestinal disturbances (heartburn, mild stomach pain, nausea).