Arthritis Drugs – NSAIDs and analgesics

Question 1

Itis

Answer 1

inflammation

Question 2

Arthro

Answer 2

joint

Question 3

Osteoarthritis (1)

Answer 3

Osteo - bone

Primary
“Wear and tear”
Related to aging

Secondary
Trauma
Disease or obesity

Pain through inflammation

Question 4

Rheumatoid arthritis

Answer 4

Rheum - flowing in a stream

Systemic auto-immune disorder
May affect other tissues

Pain through inflammation

Rheumatologists treat a range of other disorders

Question 5

Osteoarthritis (2)

Answer 5

Disease affecting synovial joints
Characterised by loss of cartilage and bone from articulating surfaces
Alteration in cartilage structure

Question 6

Why is cartilage degraded?

Answer 6

Upregulation of cytokines?
IL-1β inhibits type II collagen synthesis of hyaline cartilage
Destroy environment surrounding cartilage cells → changes to cartilage structure
Cathepsin-B can cleave aggrecan
↑Matrix metalloproteinases → breakdown of collagen → cartilage degradation

Question 7

Risk factors

Answer 7

Gender (more common in women)
Obesity
Age (> 40)
Genetic (e.g. collagen gene mutations)
Previous joint injury/ disease

Question 8

Prostaglandins

Answer 8

PGD2/ PGI2 → vasodilation
PGE2 → vasodilation, pyrogenic + (under certain conds.) anti-inflammatory effects

Potentiate effects of histamine, bradykinin
Increased permeability of venules → oedema
Increased sensitivity of C fibres (PAIN!)

Question 9

COX-1

Answer 9

‘Constitutive’
Expressed in most tissues (inc platelets)
Housekeeping’ enzyme
Protects GI mucosa
Control of renal blood flow
Initiation of labour

Question 10

COX-2

Answer 10

‘Inducible’
Inflammatory cells – induced by injury, infection, cytokines
Prod. inflamm. mediators

Question 11

COX-3

Answer 11

?

Found in CNS of some species

Question 12

The NSAIDs

Answer 12

Non-Steroidal Anti-Inflammatory Drugs (~ 50 on global market)
Aspirin
Ibuprofen*
Diclofenac
Meloxicam
Indomethacin
Many are available OTC
Most widely prescribed drugs for arthritis
Diff formulations (e.g. tablets, suspensions, gels, injections)

Question 13

Actions of NSAIDs

Answer 13

Antipyretic
inhibit actions of PGs on hypothalamus
Analgesic
reduce sensitivity of neurons to bradykinin
effective against pain of muscular/ skeletal origin
Anti-inflammatory
reduce vasodilation and decrease permeability of venules

Question 14

Other actions of NSAIDs

Answer 14

May scavenge oxygen radicals → ↓ tissue damage
Aspirin – inhibits NFκB expression → ↓ transcription of genes for inflammatory mediators
Celecoxib, diclofenac and ibuprofen - ↓ IL-6 and TNF-α in SF

N.B. only suppress signs + symptoms of inflammation – do not ↓ cytokine rel or ↓ toxins which cause tissue damage in chronic disease.

Question 15

NSAIDs (contd)

Answer 15

Variation in individual responses/ tolerance to drugs
~ 60% people respond to any NSAID
Others usually respond to certain NSAIDs
Pain relief almost immediate → full analgesic effect within a week (anti-inflamm. effect takes longer)

Question 16

Problems with NSAIDs

Answer 16

Risk of gastric ulcers
Impair coagulation
Use with caution in elderly (GI bleeding can be serious/ fatal)
Risk of CV events in patients with cardiac disease/ hypertension
May induce asthma attack, angioedema, urticaria or rhinitis

Question 17

Why the problem?

Answer 17

Many inhibit COX1 as well as COX2
PGs produced by COX1 are involved in many beneficial processes:
Production of GI mucus (protective)
Blocking ↑ risk of ulcer
Cardiovascular function : PGs (e.g. PGI2) inhibit platelet aggregation*

COX also generates TXA2, which promotes platelet aggregation.

Question 18

Solving the problem

Answer 18

COX1 and COX2 differ in structure
Should be possible to produce selective drugs
Observed that best tolerated (GI) drugs had some COX2 selectivity
E.g. meloxicam
But rofecoxib (early COX-2 inhibitor) withdrawn, as some patients died from CV complications (↓ PGI2 → platelet aggregation?)

Question 19

COX2 Inhibitors

Answer 19

E.g. celecoxib, etoricoxib
Used mainly in patients at high risk of serious GI side effects (but with little CV risk*)
Common side-effects: headache, dizziness, skin rash, peripheral oedema

*i.e. due to possible CV side-effects

Question 20

An Alternative Strategy

Answer 20

Misoprostol (synthetic PG)	
Given alongside NSAIDs
Preserves mucous lining of GI tract
Protects against ulceration
Other uses?
Side-effects: diarrhoea (can be severe), vaginal bleeding
 N.B. Precautions in women of childbearing age!
Proton Pump Inhibitors (e.g. omeprazole)
Reduce acid secretion

Question 21

Aspirin

Answer 21

Rapidly absorbed in stomach (i.e. weak acid)
Displaces warfarin bound to plasma proteins
i.e. ↑ plasma warfarin + potentiates warfarin’s anticoagulant activity!!

Question 22

Paracetamol: A Special Case

Answer 22

Paracetamol is NOT an NSAID
Why?	
It has no anti-inflammatory effect	
But...
It is analgesic, antipyretic
It suppresses PG production
Actions may involve COX, but in CNS (COX3?)
May stimulate serotonergic pathways involved in inhibition of pain sensation
Often grouped together with NSAIDs

Question 23

Paracetamol – side effects

Answer 23

Few side-effects
Chronic use of large doses → kidney damage
Toxic doses (10 – 15g) → potentially fatal liver damage (occurs 24 – 48hr after O.D.)

Question 24

Osteoarthritis – treatment options

Answer 24

Weight loss
Exercise – strengthens core muscles/ improves aerobic fitness
Suitable footwear + pacing
Joint supports/ braces
Thermotherapy/ TENS devices

Question 25

Drugs used to treat osteoarthritis

Answer 25

Paracetamol – regular dosing ± oral NSAID (with PPI*) Topical NSAID or capsaicin (esp knee/ hand) Opioid analgesic – for further relief Intra-articular corticosteroid injection → temporary benefit Joint replacement surgery (hip, knee, ankle)

Question 26

Drugs with potential benefit (1)

Answer 26

Strontium ranelate promotes osteoblast differentiation/ inhibits osteoclast activity* reduces pain* Indicated for prevention of fractures in severe osteoporosis (OP) BUT - found to ↑ risk of MI and thrombotic events so use restricted to treatment of severe OP**

Question 27

Drugs with potential benefit (2)

Answer 27

Glucosamine sulphate major constituent of ECM Present in cartilage + synovial fluid Demonstrated positive effects both in vitro + in vivo (animal models) Differing results from clinical trials – measured pain and structural improvement Overall no sig benefit but poss long-term side effects Not recommended by NICE!

Question 28

Rheumatoid arthritis

Answer 28

Causes joint inflammation, especially: Synovial membrane Tendon sheaths Bursae* Leads to proliferation of synovial membrane + erosion of cartilage/ bone Symptoms: Joints swollen + stiff (morning stiffness > 30 mins), can be painful

Question 29

Rheumatoid arthritis (contd)

Answer 29

Affects ~ 1% UK population → 1 in 3 likely to develop severe disability Autoimmune disorder → 2- 4 x more common in women Most commonly diagnosed between 40 and 60 years of age

Question 30

Rheumatoid arthritis: Treatment Options

Answer 30

``` NSAIDs/ opioid analgesics Glucocorticoids Immunosuppressants Disease Modifying Antirheumatic Drugs (DMARDS) Anticytokines ```

Question 31

Glucocorticoids

Answer 31

Naturally produced in the body – where? Used short-term – to manage flare-ups (rapidly reduce inflammation) in patients with recent-onset or established disease Long-term – if other treatment options failed - must discuss complications

Question 32

Actions of Adrenal Steroids

Answer 32

``` Two main types of action: Glucocorticoid metabolic effects anti-inflammatory immunosuppressive ``` Mineralocorticoid water & electrolyte balance

Question 33

Natural steroids

Answer 33

Hydrocortisone/ corticosterone show both (MC + GC) activities enzyme in MC-sensitive tissues (e.g. kidney) converts these to MC-inactive compounds – why? Aldosterone mineralocorticoid only

Question 34

Synthetic steroids

Answer 34

Modification of natural steroids gives: Different split of activities/potencies Varying duration of action i.e. useful to be able to manipulate steroid activity according to therapeutic needs

Question 35

Splitting activities

Answer 35

Modification of natural steroids gives: Mixed gluco-/ mineralocortiocoid activity prednisolone, prednisone Glucocorticoid activity dexamethasone, betamethasone beclomethasone, budesonide Mainly mineralocorticoid activity fludrocortisone

Question 36

Duration of action of steroids

Answer 36

Short-acting (1 -12 hrs) Cortisone/ hydrocortisone Twice daily cream or intra-articular injection Intermediate-acting (12 – 36 hrs) Prednisolone Daily oral or intra-articular injection Long-acting (36 – 55 hrs) Dexamethasone Intra-articular injection every 3 - 21 days

Question 37

Glucocorticoid actions in R.A.

Answer 37

anti-inflammatory, immunosuppressant actions: ↓ transcription of pro-inflammatory cytokines (e.g. IL-2) ↓ circulating lymphocytes inhibit phospholipase A2 → ↓ release of arachidonic acid……………. ↑ synthesis of anti-inflamm. proteins (e.g. protease inhibitors) used for asthma and ARTHRITIS…. beclomethasone, budesonide, prednisolone – stabilise mast cells (so ↓ histamine rel.)

Question 38

Unwanted effects of oral corticosteroids

Answer 38

``` Buffalo hump Moon face Hypertension Increased abdominal fat Thinning of skin Increased risk of infection Muscle wasting Poor wound healing Osteoporosis ```

Question 39

Methods of reducing side effects

Answer 39

Lower plasma concentrations → fewer side effects | Choose route of admin to achieve this (e.g. topical admin.)

Question 40

Danger of stopping steroid treatment abruptly

Answer 40

Patients on course of steroid therapy > 1 month must not suddenly stop treatment Patients on long-term therapy advised to carry card

Question 41

Disease Modifying Antirheumatoid Drugs (DMARDs)

Answer 41

Drugs with unrelated structures + diff mechanisms of action Therapy started upon definite diagnosis of R.A. → slow onset of disease Most important examples: Sulfasalazine, gold compounds, penicillamine, immunosuppressants (e.g. methotrexate, ciclosporin, azathioprine, leflunomide), anticytokines

Question 42

Sulfasalazine

Answer 42

Common 1st choice DMARD in UK Complex of salicylate (NSAID) + sulphonamide (antibiotic) Thought to act by scavenging free radicals prod by neutrophils Causes remission in ‘active’ R.A. Given as enteric-coated tablets (poorly absorbed orally) Side-effects: GI upset, headache, skin reactions, leukopenia

Question 43

Penicillamine

Answer 43

Prod by hydrolysis of penicillin 75% patients respond but therapeutic effects take weeks Thought to ↓ IL-1 generation + ↓ fibroblast proliferation → ↓ immune response Given orally – peak plasma conc → 1-2 hrs Side-effects: rashes, stomatitis (40% patients); anorexia, taste disturbance, fever, n & v Should not be given with gold compds – metal chelator!

Question 44

Gold compounds (sodium aurothiomalate/ auranofin)

Answer 44

Auranofin (oral) → inhibits induction of IL-1 + TNF-α → ↓ pain + joint swelling Sodium auranofin – deep i.m. injection Concentrate in synovial cells, liver cells, kidney tubules, adrenal cortex & macrophages Effects develop over 3 – 4 months Side-effects: skin rashes, flu-like symptoms, mouth ulcers, blood disorders (33%) Serious side-effects: encephalopathy, peripheral neuropathy + hepatitis (10%)

Question 45

Anti-malarials (chloroquine/ hydroxychloroquine)

Answer 45

↑pH of intracellular vacuoles → interferes with antigen-presenting Induces apoptosis in T-lymphocytes Usually used when other treatments fail Therapeutic effects take a month ~ 50% patients respond Side-effects: n+v, dizziness, blurring of vision – requires screening

Question 46

Anticytokine Drugs

Answer 46

Engineered recombinant antibodies → v. expensive! Use restricted to patients who don’t respond well to other DMARDs Can be given with methotrexate E.g. adalimumab, etenercept, infliximab – target TNF; rituximab, abatacept, natalizumab – target leukocyte Rs; tocilizumab - blocks IL-6 Rs → disrupt immune signaling

Question 47

Anticytokine Drugs (contd)

Answer 47

Proteins – how does this restrict admin? Given by s.c. or i.v. injection Some patients do not respond Side-effects: may develop latent disease (e.g. TB, hep B, herpes zoster, etc) + opportunistic infection; also, nausea, ab pain, worsening heart failure, hypersensitivity

Question 48

Immunosuppressants

Answer 48

Rheumatoid arthritis is an AUTOIMMUNE disorder | Suppressing the immune system will therefore suppress (but not cure) disease

Question 49

Ciclosporin

Answer 49

1st discovered in fungus Potent immunosuppressant but no effect on acute inflammation Inhibits IL-2 gene transcription → ↓ T cell proliferation Poorly absorbed orally – special formulations (capsules/ oral solutions) Accumulates in high conc in tissues (i.e. remains for some time)

Question 50

Side-effects

Answer 50

Nephrotoxicity* Hepatotoxicity Hypertension Also: nausea/ vomiting, gum hypertrophy, GI problems

Question 51

Azathioprine

Answer 51

Cytotoxic: interferes with purine metabolism → ↓ DNA synthesis Depresses cell-mediated + antibody-mediated immune reactions i.e. targets cells in induction phase of immune response Main specific effect: suppression of bone marrow – impact of this?

Question 52

Methotrexate

Answer 52

Folic acid antagonist → inhibits DNA synthesis Blocks growth and differentiation of rapidly dividing cells – other uses? Inhibits T cell activation Patients often continue treatment for > 5 years Side-effects: possibility of blood dyscrasias (abnormalities) + liver cirrhosis (requires monitoring), folate deficiency – why is this a problem? Often prescribed with a DMARD

Question 53

Leflunomide

Answer 53

Specific inhibitor of activated T cells Well absorbed orally; long t½ Side-effects: diarrhoea, alopecia, ↑ liver enzymes → risk of hepatotoxicity

Question 54

Cyclophosphamide

Answer 54

Only used when other therapies have failed Prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)

Question 55

Immunosuppressants: general problems

Answer 55

Glucocorticoids + other IS drugs: Increase risk of infection Increase risk of cancer

Question 56

NSAIDs

Answer 56

Aspirin, ibuprofen, meloxicam, celecoxib Inhibit COX enzyme → ↓ PG prod

Question 57

Corticosteroids

Answer 57

Prednisolone, dexamethasone, fludrocortisone Block gene transcription + synthesis of inflammatory proteins, immunosuppressant.

Question 58

Immunosuppressants

Answer 58

Ciclosporin, azothioprine, methotrexate, leflunomide, cyclophosphamide Inhibit DNA synthesis or T cell activation.

Question 59

DMARDS

Answer 59

Sulfasalazine, pencillamine, gold compds, anti-malarials Diff mechanisms: scavenge free radicals, ↓ IL-1, etc

Question 60

Anticytokines

Answer 60

Etenercept, infliximab, rituximab, abatacept Antibodies which bind to specific immune cells cytokines to inhibit immune response.