Pharmacotherapy in GCA and

PMRDr 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

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 PainHuman Cell

The outside of our cells is made of a chemical

called phospholipid

Arachdonic acid is formed by the

phospholipid – steroids stop this

Non-steroidals, such as diclofenac stop COX forming PG

PG1

PG2

Arachdonic Acid

COX ENZYME

An enzyme is a molecule that

transforms chemicals

PG1 protects the stomach lining and other membranes

PG2 causes inflammation and pain but protects

the heart

Cytokine

Cell damage

Human cell

Attraction of white blood cells

Corticosteroid

Immunosupression

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

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