Arthritis Drugs Flashcards
What is arthritis?
Joint inflammation
Osteoarthritis
Osteo - bone Primary “Wear and tear” Related to aging Secondary Trauma Disease or obesity Pain through inflammation
Rheumatoid arthritis
Rheum - flowing in a stream Systemic auto-immune disorder May affect other tissues Pain through inflammation tends to affect small joints first, such as in hands and feet but can affect any connective tissues (skin, CV system, lungs, muscles). Occurs because antibodies are targeted towards normal proteins in the connective tissue of joints, with the result that pro-inflammatory chemicals called cytokines are released. Causes joint inflammation, especially: Synovial membrane Tendon sheaths Bursae Leads to proliferation of synovial membrane + erosion of cartilage/ bone
Osteoarthritis is a disease affecting synovial joints
Characterised by loss of cartilage and bone from articulating surfaces
Alteration in cartilage structure
cartilage gets worn away and there are changes in the protein structure of the cartilage. As a result, the cartilage layer becomes thin and the bone underneath grows to fill the space where the cartilage was. The result is that bone spurs develop. The ends of the bone rub together and the shape of the joint changes, causing deformities. Fragments of cartilage end up in the synovial fluid, reducing its lubricant capacity. Often affects multiple joints in sufferers
Type I collagen
location- bone
function- Osteoblast differentiation from bone marrow
Type II collagen
location - cartilage function - Maintains integrity of cartilage
Aggrecan
Location - synovial membrane
Function - Maintains integrity of cartilage
Matrix metalloproteinases
Location - Synovial Tissue
Function - Degrade extra cellular matrix proteins to enable growth
Why is cartilage degraded?
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
Risk factors
Age Gender - more common in women thought to be due to a decrease in oestrogen after menopause Previous joint injury/ disease Genetic (e.g. collagen gene mutations) Obesity
The Inflammatory Response
Phospholipase A2 (PLA2) ---> Arachidonic acid ---> COX ---> Blood vessels/ local tissues/ Mast cells PGE2 PGI2 PGE2
Arachidonic acid
Arachidonic acid is a constituent of the cell membrane, derived from linoleic acid in the diet (found in vegetable and nut oils and butter).
Eicosanoids
Eicosanoids are 20 carbon fatty acids derived from the cell membrane.
PGI2
PGI2 (prostacyclin) synthesized in vascular endothelial cells
PGD2/ PGI2 → vasodilation
PGE2
PGE2 – mast cells/ macrophages and many other tissues, including those surrounding hypothalamus. i.e. blocking COX enzymes leads to a reduction in prostaglandins E2 and I2 and also thromboxanes such as TxA2.
PGE2 → vasodilation, pyrogenic + (under certain conds.) anti-inflammatory effects
COX
Cyclo-oxygenase (COX) enzymes found throughout the body
Three isoforms - COX1, COX2, COX3
All catalyse the same reaction (i.e. arachidonic acid → PGs and Txs)
‘Housekeeping’ responsibilities include regulation of blood flow/ clotting and renal function.
COX also known as Prostaglandin H synthase.
poteential effects of histamine/ bradykinin
Increased permeability of venules → oedema
Increased sensitivity of C fibres (PAIN!)
Tx
Thromboxane
COX 1
Constitutive Expressed in most tissues including platelets house keeping enzyme protects GI mucosa control of renal blood flow initiation of labour
COX 2
Inducible
Inflammatory cells – induced by injury, infection, cytokines
COX-2 is produced ‘when needed’. The products of COX-2 have roles in inflammation, fever, pain and also ovulation and uterine contraction during labour.
COX 3
Found in CNS of some species
COX-3 may be produced from the same gene as COX-1.
NSAIDs
target COX enzymes
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)
Actions of NSAIDs
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
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
NSAID response
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)
Problems with NSAIDs
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
angioedema
rapid swelling of dermis, subcutaneous tissues;
Urticaria
skin rash (hives)
Why do NSAIDs create complications?
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.
How to solve the problem that NSAIDs create
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?)
Meloxicam
Meloxicam – appears to concentrate in synovial fluid – free concentration higher than in plasma (why? Lower albumin content) At therapeutic concentrations, less GI effects than other NSAIDs and does not affect platelet function. CV complications – i.e. MI and stroke. Also problems with wound healing, angiogenesis and resolution of inflammation + more expensive than NSAIDs.
COX2 Inhibitors
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
Misoprostol (synthetic Prostaglandins)
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
Aspirin
Rapidly absorbed in stomach (i.e. weak acid)
Displaces warfarin bound to plasma proteins
i.e. ↑ plasma warfarin + potentiates warfarin’s anticoagulant activity!!
Paracetamol
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
Used as a safer (long-term) alternative to NSAIDs/ COX-2 inhibitors BUT recent studies (NICE Guideline Development Group) have queried the effectiveness of paracetamol in treating OA.
Paracetamol – side effects
Few side-effects Chronic use of large doses → kidney damage Toxic doses (10 – 15g) → potentially fatal liver damage (occurs 24 – 48hr after O.D.)
Osteoarthritis – treatment options
Exercise – strengthens core muscles/ improves aerobic fitness Suitable footwear + pacing Weight loss Joint supports/ braces Thermotherapy/ TENS devices
Drugs used to treat osteoarthritis
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)
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**
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!
Diagnosis of Rheumatoid arthritis
Symptoms presented – usually a throbbing andaching sort of pain. Often worse in the mornings and after resting, not after activity.
Stiffness - especially in the morning. Rheumatoid arthritis morning stiffness usually lasts longer than half an hour (i.e. longer than O.A.) Warmth and redness – affected joint hot, tender to touch and painful + inflammation around the joints, such as tear glands and salivary glands.
Important to diagnose RA asap.
Refer to specialist (rheumatologist) to confirm diagnosis, assess progression of disease, prescribe DMARDs to limit joint damage.* urgent referral if small joints are affected or >1 joint affected.
Diagnosis – physical examination of joints, blood tests – markers of inflammation, FBC for anaemia (associated with RA), Rheumatoid factor – present in 8/ 10 with RA but may not show up early in disease + also in some unaffected individuals; imaging – x-rays, ultrasound, MRI.
Disease progression/ control assessed by measuring levels of C-reactive protein (CRP) in the blood.
Rheumatoid arthritis treatment options
NSAIDs/ opioid analgesics Glucocorticoids ---> treatment of pain Immunosuppressants Disease Modifying Antirheumatic Drugs (DMARDS) Anticytokines ----> Limitation of joint damage *Treatment should be started within 3months of the onset of persistent symptoms
Maintenance of a healthy joint
Osteoblasts – bone formation
Expression of anti-inflammatory cytokines (IL-10, IL-11, IL-1RA)
Chondrocytes synthesize collagen matrix (anabolic)
maintenance of a healthy joint requires the correct balance of cells and chemicals (N.B. the cells present in the joint are influenced by cytokines present in the synovial fluid). If this balance is disrupted (e.g. by an enhanced immune response) then the joint will start to break down.
Destruction of a joint
Osteoblasts – bone resorption
Expression of pro-inflammatory cytokines (TNF, IL-1, IL-6)
Chondrocytes/ synovial fibroblasts secrete MMPs – break down collagen (catabolic)
Glucocorticoids
Naturally produced in the body
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
Used short-term to manage flare-ups in patients with recent-onset or established disease to rapidly reduce inflammation. Long-term treatment offered if complications have been discussed and other treatment options have failed.
Actions of Adrenal Steroids
Two main types of action: Glucocorticoid metabolic effects anti-inflammatory immunosuppressive Mineralocorticoid water & electrolyte balance Metabolic - Increase breakdown of protein and fat to release glucose. Where does this happen? (liver/ adipose tissue) Also proteins broken down – amino acids released into blood; anti-inflammatory – inhibit prod of inflammatory mediators (reminder later); immunosuppressive – inhibit NF-B which is necessary for activation of immune cells (B cells) and synthesis of cytokines.
Natural steroids
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
Aldosterone – increased reabsorption of Na and H2O in collecting duct/ DCT – inc bp.
Synthetic steroids
Modification of natural steroids gives:
Different split of activities/potencies
Varying duration of action
Duration of action of steroids
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
Nuclear receptors and steroids
Steroids must enter the cell before causing a response. They are able to do this because they are lipid (fat) soluble and are therefore able to cross the cell membrane. Once in the cytoplasm, steroids bind to free receptors to form a complex. 2 complexes join together, enabling them to enter the nucleus. Once inside the nucleus, the complex binds to DNA. This results in genes being either switched on (e.g. lipocortin-1) or switched off. When genes are switched on messenger RNA is produced, which is used to make particular proteins. Many well-used steroids work by switching off genes. These are often genes which code for proteins involved in inflammation.
i.e. takes time for steroids to have an effect.
Glucocorticoid actions in Rheumatoid arthritis
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.)
Unwanted effects of oral corticosteroids
Buffalo hump Moon face increased abdominal fat thinning of skin increased risk of infection poor wound healing hypertension muscle wasting osteoporosis
Danger of stopping steroid treatment abruptly
Patients on course of steroid therapy > 1 month must not suddenly stop treatment
Patients on long-term therapy advised to carry card
Cause suppression of normal steroid synthesis
due to excessive negative feedback
may precipitate acute adrenal failure
if exogenous steroids withdrawn abruptly, gradual reduction needed
Disease Modifying Antirheumatoid Drugs (DMARDs)
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
Sulfasalazine
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
Penicillamine
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!
Penicillamine also thought to prevent maturation and cross-linking of newly synthesized collagen (useful in scleroderma, a disease in which hard fibrous plaques occur in the skin.
Stomatitis
inflammation of mucous membranes in the mouth (gums, cheeks, etc)
Gold compounds (sodium aurothiomalate/ auranofin)
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%)
Anti-malarials (chloroquine/ hydroxychloroquine)
↑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
Anticytokine Drugs
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
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
Act as decoy receptors, mopping up naturally present TNF-alpha. i.e. TNF-alpha and interleukins released in the joints of sufferers – these chemicals (cytokines) induce COX-2 expression. Have less effect on normal immune response.
Abatacept used in combination with MTX in patients who have failed to respond to 2 DMARDs
Immunosuppressants
Rheumatoid arthritis is an AUTOIMMUNE disorder
Suppressing the immune system will therefore suppress (but not cure) disease
Ciclosporin
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)
Given to patients who have received transplants. Thought to inhibit gene transcription of the cytokine IL2.
side effects -Nephrotoxicity*
Hepatotoxicity
Hypertension
Also: nausea/ vomiting, gum hypertrophy, GI problems
Azathioprine
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
Purines are bases found in DNA which are necessary for synthesis of DNA during cell proliferation. Depresses antibody-mediated immune reactions by interfering with production of B cells and presentation of antigen to T cells (i.e. reduces proliferation of these cells).
Methotrexate
Folic acid antagonist → inhibits DNA synthesis
Blocks growth and differentiation of rapidly dividing cells
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
Leflunomide
Specific inhibitor of activated T cells
Well absorbed orally; long t½
Side-effects: diarrhoea, alopecia, ↑ liver enzymes → risk of hepatotoxicity
Cyclophosphamide
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)
