Arthritis drugs Flashcards
What are NAIDs (Non-Steroidal Anti-Inflammatory Drugs) actions?
Antipyretic - inhibit actions of PGs on hypothalamus
Analgesic - reduce sensitivity of neurons to bradykinin and effective against pain of muscular/ skeletal origin
Anti-inflammatory- reduce vasodilation and decrease permeability of venules
May scavenge oxygen radicals → ↓ tissue damage
only suppress signs + symptoms of inflammation – do not ↓ cytokine rel or ↓ toxins which cause tissue damage in chronic disease
What are side effects of 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
What causes the side effects?
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 and Cardiovascular function : PGs (e.g. PGI2) inhibit platelet aggregatio
Ibuprofen
NSAIDs
ibuprofen - ↓ IL-6 and TNF-α in SF
Aspirin
NSAIDs
Rapidly absorbed in stomach (i.e. weak acid) Displaces warfarin bound to plasma proteins (↑ plasma warfarin + potentiates warfarin’s anticoagulant activity)
Aspirin – inhibits NFκB expression → ↓ transcription of genes for inflammatory mediators
Diclofenac
NSAIDs
↓ IL-6 and TNF-α in SF
How do you solve the NSAID/ COX problem?
COX1 and COX2 differ in structure- Should be possible to produce selective drugs
Observed that best tolerated (GI) drugs had some COX2 selectivity
Meloxicam and Celecoxib
Meloxicam
NSAIDs
Function = Appears to concentrate in synovial fluid – free concentration higher than in plasma (due to albumin content). At therapeutic concentrations, less GI effects than other NSAIDs and does not affect platelet function.
Side effects = MI and stroke. Also problems with wound healing, angiogenesis and resolution of inflammation + more expensive than NSAIDs
Celecoxib
Mainly used in patients with high GI risk and low CV risk
Side effects = headache, dizziness, skin rash, peripheral oedema
Glucocorticoids, what are they? How do they work?
Work by suppressing the function of macrophages; hence reduce secretion of inflammatory cytokines
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. These drugs are also used for asthma and arthritis as they reduce histamine.
Actions of Glucocorticoids?
Anti-inflammatory, immunosuppressant actions helping reduce RA symptoms:
↓ transcription of pro-inflammatory cytokines ( IL2)
↓ circulating lymphocytes
inhibit phospholipase A2 → ↓ release of arachidonic acid
↑ synthesis of anti-inflamm. proteins (e.g. protease inhibitors)
Name the modification of natural steroid?
- Mixed gluco-/ mineralocortiocoid activity
- Glucocorticoid activity
- Mainly mineralocorticoid activity
Side effects of steroids?
- Moon face
- Buffalo hump
- Hypertension
- Thin skin
- Poor healing
- Osteoporosis
- Increased risk of infection
- Increase abdominal fat
Prednisolone
Corticosteroids Fuction = Mixed gluco-/ mineralocortiocoid activity Intermediate acting (12-36 hours) via oral or IA injection
Dexamethasone
Corticosteroids
Fuction = Glucocorticoid activity
Long acting (3-21 days)
IA injection
Fludrocortisone
Corticosteroids
Fuction = Mainly mineralocorticoid activity
Used for addisons disease
What are Disease Modifying Antirheumatoid Drugs (DMARDs)?
Drugs with unrelated structures and diff mechanisms of action, the treatment must start upon definite diagnosis of R.A. → slow onset of disease. They work by scavenge free radicals, ↓ IL-1.
Sulfasalazine
DMARD
Function = it consists of a Complex of salicylate (NSAID) + sulphonamide (antibiotic). It works by scavenging free radicals prod by neutrophils, causing a remission in active RA.
Side effects = GI upset, headache, skin reactions, leukopenia
Penicillamine
DMARD
Function = Thought to ↓ IL-1 generation + ↓ fibroblast proliferation → ↓ immune response. It is given orally, opeak plasma conc can take 1-2 hours
Side effects = rashes, stomatitis (40% patients); anorexia, taste disturbance, fever, n & v
Should not be given with gold compds – metal chelator!
Gold compounds (sodium aurothiomalate/ auranofin
DMARD
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
DMARD
Function = ↑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
What are Anticytokine Drugs?
Engineered antibodies that act as decoy receptors Mop up naturally present TNF-alpha Stop the release of cytokines and COX2 Well expensive Only for patients who cant have DMARDs
Infliximab
Etenercept
Adalimumab
Anticytokine Drugs
Target TNF
rituximab
abatacept
Anticytokine Drugs
Target leukocyte Rs
tocilizumab
Anticytokine Drugs
blocks IL-6 Rs → disrupt immune signaling
Anticytokine Drugs side effects?
may develop latent disease (e.g. TB, hep B, herpes zoster, etc) + opportunistic infection; also, nausea, ab pain, worsening heart failure, hypersensitivity
Immunosuppressants? Why are they used?
Rheumatoid arthritis is an AUTOIMMUNE disorder, Suppressing the immune system will therefore suppress (but not cure) disease
Ciclosporin
immunosuppressants - potent and poorly absorbed orally so need special capsule
Function = Inhibits IL-2 gene transcription → ↓ T cell proliferation
Side effects = Nephrotoxicity Hepatotoxicity Hypertension nausea/ vomiting, gum hypertrophy, GI problems
Azathioprine
immunosuppressants
Function = Cytotoxic: interferes with purine metabolism → ↓ DNA synthesis. Depresses cell-mediated + antibody-mediated immune reactions, it targets cells in induction phase of immune response
Side effects = suppression of bone marrow
Methotrexate
immunosuppressants
Function = Folic acid antagonist → inhibits DNA synthesis
Blocks growth and differentiation of rapidly dividing cells Inhibits T cell activation
Side effects = possibility of blood dyscrasias (abnormalities) + liver cirrhosis (requires monitoring), folate deficiency – Often prescribed with a DMARD
Leflunomide
immunosuppressants
Function = Specific inhibitor of activated T cells
Well absorbed orally; long t½
Side effects = diarrhoea, alopecia, ↑ liver enzymes → risk of hepatotoxicity
Cyclophosphamide
immunosuppressants - Only used when other therapies have failed
Function = Prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein
Side effects = Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)
