Pharmacotherapy in GCA and PMR Dr Tristan Learoyd Sunderland School of Pharmacy

Disease Polymyalgia Rheumatica and/or Giant Cell Arteritis (also known as Temporal Arteritis) physical and psychological effects Main symptoms are pain and unreasonable fatigue morning stiffness which eases as the day progresses is a significant factor along with severe pain in the shoulders, thighs and pelvic area Aetiology unknown Patients can be on complicated medication regimes Chronic condition requiring long term therapy Psychologically as think will get better next week Unknown aetiology makes targeting the disease a problem. Focus on symptoms rather than cause or prophylaxis

Pharmacotherapy Many agents used Steriods: prednisolone predominantly Bone protectants: alendronate Non-steroidal anti-inflammatories (in passing)

Prednisolone Start at a high dose and then reduced to maintenance Slow reduction 60 mg reduced as symptoms and erythrocyte sedimentation rate subsides Steady state pharmacokinetics Plasma half-life of prednisolone much shorter than biologic half-life (2.5-4 hours)

Why take some tablets once a day why some three times?

Inflammation and Pain PG1 PG2 The outside of our cells is made of a chemical called phospholipid Human Cell Arachdonic acid is formed by the phospholipid – steroids stop this Arachdonic Acid An enzyme is a molecule that transforms chemicals COX ENZYME Non-steroidals, such as diclofenac stop COX forming PG PG1 protects the stomach lining and other membranes PG2 causes inflammation and pain but protects the heart PG1 PG2

Immunosupression Attraction of white blood cells Human cell Cytokine Cell damage Corticosteroid

Immunosupression by Corticosteroids Immunosupression by stimulating intracellular glucocorticoid receptors which interferes with RNA and DNA synthesis and thus cytokine production Large initial doses as the first action of corticosteroids on the redistribution of lymphocytes to bone marrow rather than for cell lysis. High doses also inhibit t-cell production

Prednisolone Glucocorticoid effects with minimal mineralocorticoid effects - Little water retention while acting on inflammation and pain Suitable oral formulation - Is absorbed across the stomach lining Crosses blood-brain barrier Use in GCA

The blood brain barrier GCA in particular requires vascular permeation to allow vasodilatation A problem to modern therapy that relies on large proteins Steroids can pass as lipophilic and relatively small

Enteric coating A coating of Cellulose acetate phthalate A glossing of ethyl cellulose. Enteric coating releases agents in the jejunum and duodenum and not in the stomach But steroids act systemically Hypocrisy?

Enteric Coating STOMACH BLOOD VESSEL Despite the enteric coating preventing release in the stomach the drug is introduced into systemic circulation and protective factors are removed as a side-effect of the steroid’s action STOMACH BLOOD VESSEL

Osteoporosis Prednisolone has a danger of osteoporosis if taken over long periods of time, due to the reduction in osteoblast formation Osteoblasts are bone cells Bone is constantly recycled The outside of bone is spongy Has direct effect suppressing production and indirect by hormone inhibition Testosterone is produced in men and oestrogen in women, the hormones are involved in signalling bone cell production Due to corticosteroid feedback on the pituitary gland in the brain less testosterone and oestrogen are produced Due to reduced oestrogen and testosterone release, the reduction in bone cell production causes a thinning of the bone as cells are removed but not replaced

Bone protection Calcium and vitamin D involved in osteoblast (bone cell) formation and a high intake of both is recommended Biphosphonates reduce osteoblast growth and turnover Calcitonin is involved with parathyroid hormone regulation of bone turnover and calcium usage Strontium stimulates bone production and reduces turnover

Other steroid Problems Diabetes can result from prolonged use Ulceration Muscle wasting Haematological effect methotrexate Cushing’s syndrome Diminished adrenocortical function over time: so during surgery and trauma additional steroid may be required Anaesthetists must know of steroid use to prevent drop in blood pressure under anaesthetic

Some Common Steroid interactions Enhanced warfarin effects Carbamazepine induces metabolism Phenytion inducement