Drugs used in inflammation

Drugs used in inflammation

The medicines in this section include those which act against inflammation. These include drugs used to manage joint inflammation (arthritis), skin inflammation (e.g. eczema), ocular inflammation, gut inflammation (e.g. ulcertive colitis and Crohn's disease) as well as for respiratory tract and allergy-associated inflammation.

 

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Antihistamines (under construction)

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. enti-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 pruritis, 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. Citirizine is futher 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 occular inflammation associated with hay fever. 

Corticosteroids (under construction)

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.

NSAIDs (inflammation) (under construction)

NSAIDs have historically been classified according to their chemical composition, but as mechanism of action has come to the fore, this is also used to classify these drugs.

NSAIDs within classes have similar characteristics and tolerability, with little difference in clinical efficacy at equivalent doses. The prescribers’ choice will be determined by other factors such as dosing regimens, route of administration and tolerability. For example, ibuprofen and diclofenac have half-lives of just 2–3 hours, whereas the oxicams have half-lives 10 times longer.

The majority of NSAIDs are non-selective, inhibiting both cyclooxygenase-1 (COX-1) and COX-2. ‘Coxibs’ which are COX-2 selective NSAIDs were developed to limit the gastrointestinal side-effects attributed to COX-1 inhibition. Unfortunately, these have been plagued by reports of increased risk of myocardial infarction and stroke, which led to some being withdrawn from the market. However, current advice notes that non-selective NSAIDs and coxibs are viable and effective options to treat chronic pain and have manageable cardiovascular safety profiles. Prescribers are advised to be cautious when treating patients at high risk of both cardiovascular and gastrointestinal toxicity, taking in to consideration the risk of thrombotic cardiovascular events and gastrointestinal complications as well as renovascular effects and congestive cardiac failure. Aspirin is not affected by the warnings of increased cardiovascular adverse effects attributed to the other NSAIDs.

A consensus document containing prescribing guidance developed by a multidisciplinary group of experts has been published in BioMed Central (BMC) Medicine (PMID: 25857826). The published guidelines are:

  • Prescribe the lowest effective dose for the shortest period of time
  • Chronic pain: consider as required dosing only and review regularly
  • Advise patient regarding potential toxicities
  • Arrange appropriate monitoring: renal function, BP, liver function
  • Patients on aspirin: avoid traditional NSAIDs and coxibs where possible
  • Renal insufficiency: avoid where possible and in those with GFR <30 ml/min
  • Hepatic insufficiency: avoid where possible and diclofenac in particular
  • Anti-coagulation: avoid traditional NSAIDs in patients on warfarin or heparin

In the UK, NICE advises co-prescription of a proton pump inhibitor (PPI) with traditional NSAIDs and coxibs.

Many NSAIDs are available OTC, with aspirin, ibuprofen and naproxen being amongst the most commonly prescribed/used.

 

Salicylates

  • Aspirin is used to manage mild to moderate pain and pyrexia, in addition to widespread use for its anticoagulant effects in ischaemic stroke and for secondary prevention in cardiovascular disease.
  • Diflunisal (approved in the US but not in the EU or UK) is used to treat mild to moderate pain, osteoarthritis, or rheumatoid arthritis.

 

Acetic acid derivatives (generic names ending in –ac)

  • Aceclofenac (PubChem  CID 71771) is administered orally for pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.
  • Bromfenac is applied topically to the eye to control postoperative inflammation following cataract surgery.
  • Diclofenac is the most potent NSAID over a broad range of measures. It can be administered as the potassium salt for pain and inflammation of rheumatic disease and other musculoskeletal disorders, acute gout, postoperative pain, migraine. The sodium salt is additionally used to manage juvenile idiopathic arthritis, and can be applied topically for actinic keratosis and in a gel for relief of pain in musculoskeletal conditions and as adjunctive treatment in knee or hand osteoarthritis. Diclofenac sodium is also used for deep intramuscular injections used to manage postoperative pain, ureteric colic or by intravenous infusion for acute postoperative pain and prevention of postoperative pain in hospital settings. Diclofenac diethylamine is contained in some topically applied formulations.
  • Etodolac for pain and inflammation in rheumatoid arthritis and osteoarthritis.
  • Felbinac (the active metabolite of fenbufen) is used to manage pain and inflammation in musculoskeletal conditions including osteoarthritis of the hand or knee.
  • Indomethacin is prescribed to treat pain and inflammation associated with rheumatic disease, other musculoskeletal disorders, acute gout and dysmenorrhoea.
  • Ketorolac trometamol is delivered orally as short-term management of moderate to severe acute postoperative pain, and topically to the eye for prophylaxis and reduction of inflammation and related symptoms following ocular surgery.
  • Nepafenac is prescribed for prevention and treatment of ocular inflammation following cataract surgery.
  • Sulindac is administered orally to manage pain and inflammation in rheumatic disease, other musculoskeletal disorders and acute gout.

 

‘Profen’ class (arylpropionic acid or propionic acid derivatives)

  • Dexibuprofen is administered orally to manage pain and inflammation e.g. for osteoarthritis, other musculoskeletal disorders, dental pain and pain and inflammation in dysmenorrhoea.
  • Dexketoprofen is administered orally for short-term treatment of mild to moderate pain including dysmenorrhoea.
  • Fenoprofen is administered orally for mild to moderate pain and pain and inflammation in rheumatic disease and other musculoskeletal conditions.           
  • Flurbiprofen is administered orally to manage pain and inflammation in rheumatic disease and other musculoskeletal disorders, migraine, postoperative analgesia, mild to moderate pain including that of dysmenorrhoea. Flurbiprofen lozenges can be used to provide sore throat relief.
  • Ibuprofen is administered orally to manage pain and inflammation of various aetiologies, including pain and moderate/severe rheumatic/musculoskeletal inflammation.
  • Ketoprofen is administered orally to provide relief of pain in musculoskeletal disorders, rheumatic inflammation, dysmenorrhoea, acute gout etc.
  • Naproxen is administered orally to manage pain and inflammation in rheumatic disease, other musculoskeletal disorders, dysmenorrhoea and gout.
  • Tiaprofenic acid is prescribed to manage pain and inflammation in rheumatic disease and other musculoskeletal disorders. It may cause severe cystitis, so is contra-indicated in patients with urinary-tract disorders. Advise patients to cease medication if urinary-tract symptoms develop.

 

Coxibs (COX-2 selective)

  • Celecoxib is administered orally to manage pain and inflammation associated with osteoarthritis, and rheumatoid arthritis (RA), and for ankylosing spondylitis.
  • Etoricoxib is used to manage pain and inflammation in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and acute gout
  • Parecoxib is a water soluble prodrug of valdecoxib. It is used for short-term management of acute postoperative pain.

Note: Parecoxib and etoricoxib are both licenced in the EU but have been withdrawn from the US market.

 

Enolic acid (oxicam) derivatives

  • Meloxicam is prescribed to relieve pain and inflammation in rheumatic disease, osteoarthritis and ankylosing spondylitis. It can be prescribed for juvenile idiopathic arthritis and other musculoskeletal disorders in children (aged 12-17) who are intolerant to other NSAIDs.
  • Piroxicam is administered orally to manage pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. For these indications prescribing is usually initiated by a specialist clinician. It can also be applied topically to the skin to provide pain relief in musculoskeletal conditions and adjunctively for inflammation relief in knee or hand osteoarthritis.
  • Tenoxicam is prescribed to manage pain and inflammation in rheumatic disease and acute musculoskeletal disorders.

 

Anthranilic acid derivatives (fenamates)             

  • Mefenamic acid is prescribed for relief of pain and inflammation of rheumatoid and osteoarthritis, postoperative pain, dysmenorrhoea, etc.
  • Tolfenamic acid is prescribed to manage acute migraine.

 

Others

  • Nabumetone is the only 1-naphthaleneacetic acid derivative NSAID. It is sometimes included in the acetic acid derivative class. It is prescribed to treat severe and persistent pain and inflammation in osteoarthritis and rheumatoid arthritis.
  • Acemetacin is a glycolic acid ester of indomethacin, administered orally for pain and inflammation in rheumatoid arthritis and other musculoskeletal disorders, and postoperative analgesia.
  • Benzydamine hydrochloride is administered orally (as mouthwash or oromucosal spray) to treat painful conditions of the oropharynx.

Aminosalicylates (under construction)

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

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).