Transcript Pharmacotherapy in GCA and PMR

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
Pharmacotherapy
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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
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
PG1 protects the stomach lining
and other membranes
COX
ENZYME
PG1
Non-steroidals, such as diclofenac
stop COX forming PG
PG2
PG2 causes inflammation and
pain but protects the heart
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 sideeffect 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
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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