pharmacotherapy in gca and pmr dr tristan learoyd sunderland school of pharmacy
TRANSCRIPT
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