Pharmacology - Inflammatory Arthritis

Pharmacology

·       NSAIDS

·        Action: Many! Inhibit PG synthesis by inhibiting cyclo-oxygenase (converts arachidonic acid to PGG2 and PGH2): 

o  COX-1: present in blood vessels, stomach, kidney (eg might actually help in heart disease – eg aspirin) 

o  COX-2: induced during inflammation ® PGs (eg Celecoxib/Celebrix and rofecoxib/Vioxx)

·        Effects:

o  Analgesic: Effective against pain where PGs sensitise nociceptors

o  Anti-inflammatory: Reduce vasodilation, oedema, pain.  Effect may not be clinically obvious for 2 â€“       3 weeks

o  Antipyretic: acts in hypothalamus

·        Pharmacokinetics: well absorbed, no first pass metabolism (except aspirin), highly protein bound

·        Side effects:

o  ­ Risk in elderly

o  GI: dyspepsia, mucosal irritation, ulceration (relative risk 5 times, ­­ if on warfarin, etc) 

o  Renal: Little effect on renal function in normal people. If chronic renal impairment, CHF, gout, or longer T½ NSAIDs then Na retention and oedema in 3 – 5%

o  Skin: rashes, urticaria, photosensitivity and erythema multiform 

o  Other: headache, ¯platelet function ® ­bleeding time, blood dyscrasias (aplastic anaemia with indometacin and phenylbutazone)

·        Interactions:

o  ¯ Antihypertensive effect of ACE inhibitors

o  ¯Diuretic action of frusemide and thiazide diuretics 

o  ­Methotrexate levels

o  Not if on anti-coagulants ® GI bleed

·        Patient instructions: Only take them PRN to avoid risk of bleed – so don‟t take them on good days. Watch for abdominal pain, black stools. Smoking and alcohol ­ the risk. Don‟t supplement them with OTC NSAIDs

·        Commonly used NSAIDs:

o  Salicylates: Aspirin (not in kids) and Diflunisal

o  Propionic Acids (better tolerated and more sensitive for COX-2): Ibuprofen, Naproxen

o  Pyrazoles: Phenylbutazone

o  Acetic Acids: Indometacin (potent, CNS side effects), sulindac

o  Paracetamol (no anti-inflammatory or GI effects)

Other Pain relief

·        Amitriptyline: a TCA which in low dose has pain modifying effects

·        Tramadol: opiod analgesic with less respiratory depression, ¯constipation and ¯addiction

Immune Suppressive Drugs

·        For acute inflammatory problem (arthritis, connective tissue, etc)

·        Prednisone: 60 mg/day starting dose

·        Methylprednisolone (iv)

Disease Modifying Anti-Rheumatic Drugs (DMARDs)

·        Aim: to suppress inflammatory activity ® ¯destructive changes (NSAIDs reduce inflammation but don‟t act on the pathway that leads to joint destruction) 

·        Indicated for patients at an early stage with high markers of disease activity Þ don‟t wait for RF, nodules or erosions 

·        Effect:

o  Suppress inflammatory activity

o  Reduce the need for NSAIDS and corticosteroids which have greater potential toxicity

·        First line agents (high efficacy especially in combination, low toxicity):

o   Sulphasalazine: start low, increase to 2-3g per day.  Best tolerated and most often used.  Effect 

o   after 3 – 6 months. SE: nausea, rashes, ¯sperm count, hepatitis, oral ulcers, rarely: blood dyscrasia, Stevens-Johnson, neutropenia, monitor CBC and LFTs 

o   Methotrexate: Takes several months to work.  Action: ¯IL-1, ­IL-10, ¯neutrophil chemotaxis.

o   SE: nausea, bone marrow suppression, GI ulceration, teratogenic.  Inhibits folate metabolism ®

o   give folic acid 5 – 10 mg/wkly, rare: irreversible liver toxin.  Monitor CBC, LFTs, Cr

o   Antimalarials: Hydroxychloroquine: weak disease modifying drug, doesn‟t stop periarticular

o   osteopenia.  SE: nausea, rash, headache, tinnitus.  Rarely: bone marrow suppression, corneal & 

o   retinal damage. Monitor: Cr and 6 – 12 monthly ophthalmological review. Chloroquine more toxic. 

·        Others:

o   Gold: Sodium Aurothiomalate / Myocrisin.  Similar efficacy to Sulphasalazine/methotrexate but 

o   more toxic. When it works it works well. Action: accumulates in macrophages. SE: rash thrombocytopenia, nephrotic syndrome, proteinuria. Not with allopurinol, SLE, breast feeding, liver/renal disease. Monitor CBC, Cr, Urine dipstick for protein 

o   Cyclosporin A: SE nephrotoxicity

o   Salazopyrin

o   Beneficial but don‟t alter progression of radiological changes:

§  Azathioprine 

§  D-Penicillamine.  SE: ¯marrow, proteinuria, ¯taste, oral ulcers, myasthenia, Goodpasture‟s

·        The future: anticytokine therapy: eg against Tissue Necrosis Factor