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Transcript
Drug treatments for Rheumatoid
Dr Steve Jones
Consultant Rheumatologist
15 March 2012
Drug action (1) – Enzyme blockers
Enzymes – chemical reactions
cell metabolism
Examples:
Methotrexate
Non-steroidals
Drug action (2) – cell signalling
(e.g. hormones, growth factors, immune system)
Examples:
Positive signal Steroids
Codeine
Signal blockers Anti-TNFs
Drug effect
depends on
concentration …
… determined by
balance intake &
metabolism
Science Recap
Most drugs work by blocking enzymes (cell function/metabolism)
or interfering with cell signalling (increase/decrease)
Drugs work best at specific concentration in body/tissues
- Need for regular dosing
- Differences in absorption/breakdown (genetics, disease)
affect ‘steady state’ concentration
too low  ineffective: too high  side effects
Some drugs are “stored” in body tissues  prolonged effect
(Methotrexate - 1-2 weeks. Bisphosphonates (Alendronate etc) weeks, months)
Analgesics
“pain killers” - work on brain, not joints.
Paracetamol - max 4g daily (overdose  liver damage)
• safe but weak analgesic
Opiates - derivatives of Morphine (‘opium’)
• naturally occurring system “endorphins” (pain/stress response)
• act via receptors on nerve cells - pain system + others
• including nerve cells controlling gut propulsion.
Opium
poppies
Opiates – potency
weak
medium
Dextropropoxyphene Dihydrocodeine
Codeine
Tramadol
Buprenorphine
strong
Fentanyl
Morphine
Oxycodone
Depends on dose:
200mg Codeine =
Max 1.2x
100mg Tramadol = 10mg MST (Morphine)
Max 4x
Max 20x (+)
Traditional : ‘Pain ladder’ – escalate between groups
But : M, K, D receptor types
Codeine, Tramadol – M, Buprenorphine – Dm, Oxycodone – Km
overlap  use in combinations
Opiates (3) Fixed combinations with Paracetamol
• ALL MAX 8/d
Co-codamol (Codeine/Paracetamol)
8/500 (8mg Codeine, 500mg Paracetamol) - non-prescription
15/500 (15mg Codeine)
30/500 branded- Kapake, Solpadol, Tylex : identical
Co-dydramol (Dihydrocodeine/Paracetamol)
7.6/500 - non-prescription
10/500 (usual) - equivalent to Cocodamol 15/500
20/500 “Remedeine” (equivalent to Kapake)
Tramacet (37.5mg Tramadol/325mg Paracetamol)
Opiate Combinations:
Plusses - easy to take
Minuses - possible Paracetamol overdose >8/d
Inadequate analgesia (8,15,30?)
Inflexible dosing
In higher strengths (e.g. Cocodamol 30/500)
: one tablet every 2-3 hours better than 2 every 4-6
Opiates (5)
S/E:
• nausea, constipation – GI
• drowsiness – brain
• skin (nerves) – itching (antihistamines)
Constipation - worst with Codeine
 use softeners (eg lactulose) , and laxatives (senna)
‘Targinact’(Oxycodone + Naloxone) – expensive!
?addiction - rare - psychological “abuse”
high doses/long time - physical: “cold turkey”
dependence ≠ addiction
Alternate delivery systems:
Patches - drug enters bloodstream through skin
Buprenorphine (BuTrans, Transtec)
Fentanyl (Durogesic)
• less GI S/E
• convenient (1, 2/week : variable doses)
• occasional skin reactions, can fall off
• relatively expensive
Sublingual – under tongue (Buprenorphine)
Buccal – inside cheek (Fentanyl – cancer pain only)
 rapid blood peak (often causes nausea)
Suppositories (Morphine)
NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
- symptomatic treatment
Related chemically to Aspirin
Weak analgesic (= Paracetamol, low dose Codeine) – brain, joints
Antipyretic (fever) - brain
Anti inflammatory – joints
• Use instead of / additional to Paracetamol, Opiates
NSAIDs work by :
Inhibiting COX enzyme (produces “prostaglandins”)
- increase bloodflow and tissue fluid (inflammation)
=> swelling, heat & stiffness
- sensitise pain nerves (inflammation)
BUT: COX also –
• needed for gastric mucus production “COX1”
(dyspepsia, ulcers, stomach/bowel bleeding)
• needed for kidney blood flow regulation
(hypertension, fluid retention, kidney impairment)
• involved in blood clotting (platelets)
(heart attack & strokes)
NSAIDs (3)
“Standard”: Ibuprofen, Diclofenac, Naproxen, Indometacin
“COX2”:
‘coxibs’
Meloxicam (?)
Rofecoxib (Vioxx) - withdrawn (& others)
Etoricoxib - (Arcoxia)
Celecoxib (Celebrex)
Coxibs “kinder on stomach”
but: standard NSAID + Omeprazole cheaper
routine - age > 60, history indigestion/ulcers
NSAIDs (4)
Benefits - additional pain relief, good for swelling/stiffness
Problems -
Control symptoms of inflammation only,
not process (exception- gout)
Anti-inflammatory potency = Side effect potency
Cardiovascular S/E –
Small increase heart attacks, strokes (controversial!)
?Naproxen, lower doses safest
Interfere with Aspirin for angina
Aggravated by hypertension & fluid retention
Corticosteroids (“steroids”)
Prednisolone : Deflazocort : Dexamethasone
Mimic Cortisol (naturally occuring steroid hormone)
• produced from adrenal glands
Basal - essential to health (= 1-2.5mg Prednisolone/d)
(normal cell metabolism, blood pressure, salt balance)
Elevated  stress response (infection, trauma..)
Mobilises sugar + fat + protein reserves (repair)
Anti-inflammatory. Anti-fatigue. Increases appetite.
Steroid Effects:
Low doses (7.5mg or less) -
Anti-inflammatory
(cell function and mobilisation)
Higher doses -
Immunosuppressant
Anti-allergy
Uses:
rheumatic diseases (RA, PMR, SLE…)
inflammatory lung, liver, bowel, brain, muscle, skin disease
Benefits : control disease process, not just symptoms = ‘DMARD’
rapid onset action (24-48 hrs)
Steroids: Rheumatology Uses
- courses for flares or disease stabilisation with DMARD
Flares -
usually only need 10-15mg Prednisolone daily
(not 30mg given for COPD/asthma)
Injections -
IM - (Kenalog, Depomedrone) - typically last 4 weeks
IA - into joints (4-6 wks : need control disease as well)
Infusion (drip) -
for severe flares
as part of immunusuppressive regime
(vasculitis, kidney disease)
to reduce allergic side effects (Rituximab)
Steroid S/E (1):
“Cushings disease”
- Excess Cortisol due to adrenal tumour
 permanent “stress response”
•
•
•
•
•
•
Weight gain (appetite and metabolism changes)
Thinning skin and bones/osteoporosis - muscle weakness - protein
Increased blood sugar (diabetes) and fats (cholesterol)
Insomnia and mood changes
Dyspepsia and peptic ulcers (NSAID-like)
High blood pressure, fluid retention
• Increased infections (higher doses)
skin, chest, urine (immunosuppression)
Side effect risk = Dose x Time (patient sensitivity varies)
Steroid Side Effects (2):
“Addisons disease” - acute Cortisol deficiency
(adrenal, pituitary gland damage
LONG TERM STEROID USE)
• inability to mount stress response to trauma, infections
• severe lethargy, fatigue, hypothermia
• low blood pressure, low blood sugar/salt
• severe cases  cardiovascular collapse
DO NOT STOP STEROIDS SUDDENLY (“physical dependence”)
- Carry Steroid card/alert bracelet
- Only adjust steroid doses after medical advice
- May need slow tail to stop (1mg/month reduction)
- IV replacement (surgery)
All patients on regular steroids need:
monitoring blood pressure, sugar and cholesterol
screening and treatment for osteoporosis prevention
? Omeprazole (PPI) for peptic ulcer prevention
& regular review to minimise steroid dose/stop if possible
Side effects unlikely from IA use (joint injections)
- may get with repeated IM use
DMARDs “Disease modifiers”
Control underlying disease process. NOT CURE.
Preventative - need taking regularly (even if disease inactive)
Effects - slow acting (disease  inflammation  symptoms)
- reduce symptoms and signs inflammation
- reduce/prevent longterm joint damage (disability)
- reduce medical complications (including heart)
- reduce systemic upset (fever, anaemia, fatigue..)
DMARD Types:
1) Chemicals (‘small molecules’) : taken orally
Methotrexate, Azathioprine, Leflunomide, Cyclophosphamide
“antimetabolites”
Block enzymes involved in cell growth/division
 main effects on actively dividing cells
•
•
•
•
•
Immune cells (lymphocytes) - desired effect
Bone marrow (white blood cells, red cells)
Gut lining cells. Liver cells (metabolically active)
Cancer cells (chemo)
Foetus
Hence side effects -
GI upset (dyspepsia, nausea, mouth ulcers, diarrhoea)
Blood problems (anaemia, low WCC, platelets)
Liver inflammation (Methotrexate & alcohol also)
(Leflunomide &
?Infections
Avoid pregnancy (Azathioprine relatively safe)
Side effects worse with higher doses  need slow dose escalation
Also problem with slow metabolisers:
Azathioprine - genetic test
Allopurinol
Methotrexate - kidney disease
NSAID. Age
Leflunomide - excreted in bile and reabsorbed
(drug persists even when stop taking)
Use - singly, work better in combination
Methotrexate and Leflunomide most effective
Methotrexate best tolerated antimetabolite (+ Folic Acid)
Other DMARDs (weaker - different mechanisms)
- Mild disease or drug combinations
• Sulfasalazine - salicylate and antibiotic (rash)
• Gold & Penicillamine - kidney problems, rashes
• Hydroxychloroquine – eye (rare)
Advantages –
Oral
Relatively effective
Cheap
Variable dosing
Infection rate similar
(stop in severe)
Disadvanges Slow onset action (weeks)
GI side effecs common (?switch to injectable)
Variation Methotrexate absorption
‘Antimetabolite’ effect limited by S/E
● Incomplete control of severe cases
● Incomplete prevention of joint damage
Blood toxicity difficult to predict; rare cases fatal
DMARD types
2) Proteins : “Biologics”
Like insulin - produced by ‘genetic engineering’
“brewed” - cell culture, not chemically synthesised
 intrinsically expensive to produce
All protein drugs digested by oral route (= “steak”)
need giving parenterally (drip, subcut)
BIOLOGIC DRUG TARGETS
Types –
Anti-TNFs
(cell signal)
Infliximab
Etanercept
Adalimumab
Certolizumab
Golimumab
Anti B cell (antibodies)
Anti T cell (“helper”)
Anti IL6 (signal)
Rituximab
Abatacept
Tocilizumab
* ALL SUPPRESS IMMUNE SYSTEM FUNCTIONS *
(Infection risk!)
Biologics-
Advantages:
more effective than conventional DMARDs
(symptoms, joint protection)
Disadvantages:
cannot be used together (with other biologics)
increased common & rare infections (TB)
Must stop drug during infection/surgery (flare risk)
? Patients with chronic infections
(bronchiectasis, COPD, bone & joint, TB, hepatitis)
COST - rationing (“NICE guidelines”)
?? long term side effects  BSRBR
Recap1:
Analgesics (Pain killers) “as required”
Paracetamol, Opiates
Work on brain, not joints
Work best taken regularly (as all drugs) when needed
Can use opiates in combination (eg. Butrans patch and Cocodamol)
NSAIDs (anti inflammatories ) “as required”
Reduce pain, stiffness, swelling joints
No effect on disease process/joint damage
Improve quality of life/disability
Common side effects due to natural function of drug
(GI/ulcers; hypertension - fluid; bleeding/clotting problems)
Cannot mix with each other (avoid Nurofen/Ibuprofen and Naproxen)
Recap2:
DMARDs (including steroids) - “regular”
Control disease process, secondary benefits swelling and pain
Slow acting. Can use in combination
Variably reduce joint damage, medical complications
Regular monitoring essential
Gradual dose increase reduces S/E
Slow tail off steroids (don’t run out!)
Biologics: newer DMARDs
Genetically engineered proteins (not oral)
More effective, less side effects
Use limited by expense
Need to stop during significant infections
May get “unusual” side effects (TB, MS) - but rare
Recap3: OTHERS
Coanalgesics (Amitriptyline, other antidepressants, Gabapentin etc)
• Reduce “nerve pain”
• Aid sleep (non-addictive)
Drugs for medical complications
- (control cholesterol & blood pressure; prevent osteoporosis)
Supplements:
Vit D/calcium
Fish oils?
Glucosamine/Chondroitin?
Iron deficiency common (NSAIDs)
SOME PRACTICAL ISSUES
Avoiding Side Effects : Minor
Is it due to drug?
Common SE - Pharmacist/GP, ArthResUK leaflets, helpline
Package inserts - list all possible side effects
Statistical significance ≠ clinical
(e.g. trial drug headache 15%, placebo 10% - only 1/3 HA due to drug)
Is it due to formulation/brand? “Excipients”
Could I get used to the drug? Reduce dose
If in doubt: stop drug few days then rechallenge
GI intolerance:
Take with food (absorption) Injections
Slower dose increase
Patches
Split dose (Methotrexate, Sulfasalazine)
Enteric coated/slow release
Alcohol and tobacco …….
GI intolerance with multiple drugs:
Marker of underlying problem 
Hiatus hernia, reflux, ulcers, Helicobacter, IBS
?diet
Can I reduce dose?
Analgesics/NSAID - need may vary with time
(flares/remissions/weather)
Work quickly - no harm in temporary reduction
Consider non-drug methods:
(rest, relaxation, hot/cold, rubs, splints, TENS ……)
DMARDs -
? lower dose combinations
may reduce during remission, without flare
Avoiding major S/E
Illness, drug interactions & new medications
(affect metabolism/drug levels)
Fever/chest infections - dehydration
Urine infections - transient reduction kidney function
Antibiotics - liver test problems, direct drug interactions
‘Red flags’
• significant abdominal pain/jaundice
• abnormal bruising or bleeding
• serious or prolonged infection, high fever
• unexplained breathlessness
• protracted vomiting or diarrhoea
• severe rash or oral ulceration
Avoiding major s/e 2
Immunosuppressants/biologics:
Immunisation status? (avoid live vaccines)
Annual flu jabs
Avoid contact with chickenpox/shingles
Tropical disease risk (TB, Malaria…)
Biologics - stop during any infection/prior to operations
(especially orthopaedic)
** Attend regularly for blood monitoring checks **
Why is my drug not working?
What are your expectations?
DMARDs take weeks to work …….
Steroids are poor painkillers …..
Analgesics work better if taken regularly ……
Is it really not working?
Is the problem inflammation (stiffness, swelling) or pain
(tenderness)?
Is the problem due to my Rheumatoid?
Coexisting or secondary osteoarthritis
Back pain – usually isn’t
Soft tissue problems (tennis elbow, bursitis)
Why is my drug not working? 2
Are you taking enough (dose, route, genes, weight)?
Primary vs secondary failure?
DMARDs - rule of 1/3’s
Biologics “diminishing returns” 1st-3rd anti TNF
HACA - Infliximab
NEW DEVELOPMENTS
1) Drug use
Minimise Inflammation x Time  reduces damage
Early recognition RA and specialist treatment
Objective measure disease activity (DAS)
Frequent regular follow-up (early or persistent disease)
“Treat to target” - remission ideally
Use rapidly escalating dose of DMARD combinations
- usually including Methotrexate
Temporary use steroids for rapid control (IM > oral)
Use minimum effective doses NSAID/anagesics - reduce s/e.
2) New Drugs
Chemicals ‘small molecule’ : tablets
- inhibitors of TNF production/metabolism
(one effect of steroids…)
several under investigation (lab/animal study)
- lymphocyte activation blockers
‘JAK kinase inhibitor’ (Tofacitinib)
available EU/UK late 2012 (then NICE..)
‘Syk kinase inhibitor’ (Fostamatinib)
works in RA but unacceptable S/E
2) New Drugs
Biologics
- other cell signal blockers (immunosuppressants)
IL6 (Tocilizumab) – in use
IL23 (Ustekinumab) – psoriasis ? Psoriatic arthritis (trials)
IL17 (Secukinumab) – trials RA, PsA, AS
IL18 – under development
* Potential problem – all similar to currently available drugs
- ‘Biosimilars’ (? cheaper, treat more people)
Enbrel patent to 2028 : Humira to 2017
- Denosumab (biologic osteoporosis treatment)
high doses reduce RA bone erosion/joint damage
(preliminary, not yet licenced for RA…)
2) New Drugs
Cancer Biology (potential use in arthritis – yrs)
Abnormal cell growth
New blood vessels
Connective tissue damage (tumour invasion & spread)
e.g. experimental MMP’ase inhibitors (enzymes break
down bone  tumour spread, also RA erosions)
- Lung cancer trials
“Personalised medicine”?
Gene screening for - best drug to use (speed of effect, cost)
- reduced risk of side effects
So far lots of research but no definite pointers
(Rituximab - works better if seropositive- not absolute)
Clinical research?
 best use of existing drugs
(current order of biologics use in UK determined mainly by
cost …)