2 Arthritis Drugs – NSAIDs and analgesics Flashcards
Objectives
To define arthritis and its symptoms
To understand the basic inflammatory response
To consider treatments for inflammation
To understand the mechanism of action of NSAIDs + their side effects
To consider alternative treatment options
What is arthritis?
Arthro - joint
Itis - inflammation
Causes pain
Affects mobility
Affects 10% of World’s population. A very debilitating condition, often with an unpredictable course. For this reason, it can be difficult to hold down a job because it isn’t clear when symptoms will get better or worse.
Causes pain and affects ability to carry out day-to-day activities. Can also affect mood, sleep and coping strategies.
Arthritis
- 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
Rheumatologists treat a range of other disorders
Very common in the elderly population – related but not caused by aging. Bones may become brittle and develop microfractures. RA 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.
Osteoarthritis
Disease affecting synovial joints
Characterised by loss of cartilage and bone from articulating surfaces
Alteration in cartilage structure
1 Bone 2 Cartilage 3 Cartilage worn away 4 Remnants of cartilage in synovial fluid 5 Destruction of cartilage
OA affects synovial joints – examples? Wrist, elbow, shoulder, knee, fingers, feet, spine. OA alters the repair process which occurs after trauma so that insufficient repair may occur.
These joints have a layer of cartilage around the ends of the articulating bones – why? In OA, this 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 – why might this be the case?
Normal maintenance of joint structure
Protein - Location - Function
1 Type I Collagen - Bone - Osteoblast differentiation from bone marrow
2 Type II Collagen - Cartilage - Maintains integrity of cartilage
3 Aggrecan - Synovial Membrane - maintains integrity of cartilage
4 Matrix metalloproteinases - synovial fluid - Degrade ECM 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
Obesity Age (> 40) Genetic (e.g. collagen gene mutations) Previous joint injury/ disease Gender (more common in )
Why more common in women? Thought to be due to a decrease in oestrogen after menopause. Genetic link – more common if siblings have it.
Not CAUSED by age + may not get worse.
The Inflammatory Response
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 are 20 carbon fatty acids derived from the cell membrane. PGI2 (prostacyclin) synthesized in vascular endothelial cells; 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. COX also known as Prostaglandin H synthase.
Prostaglandins
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!)
What is the benefit of this response?
i.e. enables white blood cells to reach site of injury/ infection.
Cyclo-oxygenase (COX) enzymes
Three isoforms: Cox1 constitutive expressed in most tissues (inc platelets) Housekeeping enzyme Protects GI mucosa Control of renal blood flow Initiation of labour
Cox 2 Inducible
inflammatory cells induced by injury, infection, cytokines
prod. inflamm mediators
Cox 3 ?
Found in CNS - in some species
All catalyse the same reaction (i.e. arachidonic acid → PGs and Txs)
Tx = Thromboxane
Found throughout the body. All three isoforms very similar in their gene sequence and protein structure. ‘Housekeeping’ responsibilities include regulation of blood flow/ clotting and renal function. It is therefore constitutively expressed (produced all the time) whereas COX-2 is produced ‘when needed’. The products of COX-2 have roles in inflamm, fever, pain and also ovulation and uterine contraction during labour. COX-3 may be produced from the same gene as COX-1.
COX: a target for NSAIDs
The NSAIDs
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)
Ibuprofen derived from propionic acid as opposed to salicyclic acid.
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
i.e. central actions – spinal cord damage causes inc COX-2 → PG release → inc pain transmission (blocked by COX inhibition)
Other actions of NSAIDs
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.
Oxygen radicals are chemically reactive molecules which are formed naturally as a byproduct when oxygen is metabolised (e.g. in respiration). NF-kB is a protein complex which causes DNA transcription in response to cytokines, stress, etc.
NSAIDs (contd)
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 the problem?
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.
Solving the problem
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 – 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.
N.B. PGI2 is a potent vasodilator as well as an inhibitor of platelet aggregation. Blocking COX-2 clearly has a large effect on blocking formation of PGI2 (and possibly a lesser effect on platelet-aggregating TXA2) and therefore shifts the balance in favour of platelet aggregation.
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
i.e. due to possible CV side-effects
An Alternative Strategy
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
Can you think of another use of synthetic prostaglandins?
Misoprostol – PGE1 analogue. Inhibits gastric acid secretion and may stimulate increased mucus production. Also used to induce abortion!
Aspirin
Rapidly absorbed in stomach (i.e. weak acid)
Displaces warfarin bound to plasma proteins
i. e. ↑ plasma warfarin + potentiates warfarin’s anticoagulant activity!!
i. e. warfarin not active until free from plasma proteins.
Paracetamol: A Special Case
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
i.e. COX-3 isoform discovered in CNS of some species. May act to inhibit reuptake of endogenous cannabinoids (e.g. anandamide) in the sc/ brain.
N.B. 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
Weight loss
Thermotherapy/ TENS devices
Joint supports/ braces
Suitable footwear + pacing
N.B. Exercise is a core treatment and involves strengthening of core muscles and improving general aerobic fitness. Other positive behavioural changes, such as weight loss, use of suitable footwear and pacing, are appropriately targeted
Patients should be reviewed regularly.
Thermotherapy – hot or cold packs. Braces/ joint supports. TENS devices (initially loaned to patients).
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)
PPI = Proton Pump Inhibitor. i.e. Glucocorticoids are powerful anti-inflammatory drugs. Narcotics stimulate numbness and therefore reduced perception of pain and include drugs from marijuana to amphetamines to cocaine. Their use is controversial. N.B. Current NICE guidelines suggest that patients be referred for surgery before symptoms become movement is too limited and pain severe. Hip and knee replacements have become common surgery in UK (at least 50,000 hip and 70,000 knee replacements/ year) and the death rate from surgery is low. Improves QoL and last up to 20-30 years. Ankle replacement is a much newer operation – reduces pain but does not tend to increase mobility of joint.
2008: Oral analgesics
1.5.1 Healthcare professionals should consider offering paracetamol for pain relief in addition to core treatments (see recommendation 1.2.5); regular dosing may be required. Paracetamol and/or topical non-steroidal anti-inflammatory drugs (NSAIDs) should be considered ahead of oral NSAIDs, cyclo-oxygenase 2 (COX-2) inhibitors or opioids. [2008]
1.5.2 If paracetamol or topical NSAIDs are insufficient for pain relief for people with osteoarthritis, then the addition of opioid analgesics should be considered. Risks and benefits should be considered, particularly in older people. [2008]
Topical treatments
1.5.3 Consider topical NSAIDs for pain relief in addition to core treatments (see recommendation 1.2.5) for people with knee or hand osteoarthritis. Consider topical NSAIDs and/or paracetamol ahead of oral NSAIDs, COX-2 inhibitors or opioids. [2008]
1.5.4 Topical capsaicin should be considered as an adjunct to core treatments for knee or hand osteoarthritis. [2008]
There have been published randomised controlled trials with interventions targeting structural components of cartilage (glucosamine sulphate) and bone (strontium ranelate). However, several limitations have been identified with the glucosamine sulphate studies, and it is unclear whether cardiovascular concerns will prevent approval of strontium ranelate for treating osteoarthritis.
Drugs with potential benefit (1)
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**
Drugs with potential benefit (2)
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!
N.B. in vitro studies used several different cell lines and very high doses of GS; animal models included rodents and horses; clinical studies – patients responded better in industry-sponsored trials than in independent trials!
Rheumatoid arthritis
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
Usually affects joints on both sides equally and symmetrically. Small joints (e.g. fingers) often affected first, followed by knees/ shoulders – muscle ache. N.B. Can be distinguished from osteoarthritis because morning stiffness lasts longer + may also cause inflammation of tear glands, salivary glands, the lining of the heart and lungs, and blood vessels. Joints also feel hot and tender.
Cells in the synovial membrane proliferate, forming a spur into the articulating surface of the bones. This causes inflammation as the bones rub together.
*Bursae are filled with synovial fluid + provide a cushion between bones and tendons and/or muscles around a joint. This helps to reduce friction between the bones and allows free movement.
Rheumatoid arthritis (contd)
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
Estimated to affect 422,000 in UK. i.e. more common in pre-menopausal women. One third stop work within 2 years of diagnosis. Total cost to UK = about £2.4 billion / year.
Higher risk if present in previous generations and some forms more prevalent in smokers.
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 Immunosuppressants Disease Modifying Antirheumatic Drugs (DMARDS) Anticytokines
*Treatment should be started within 3months of the onset of persistent symptoms
Glucocorticoids
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
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
i.e. Aldosterone → ↑ Na+ reabsorption in C.D. → ↑B.P.
i.e. 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.
Aldosterone – increased reabsorption of Na and H2O in collecting duct/ DCT – inc bp.
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
i.e. have both mineralo- and glucocorticoid actions but broken down in MC-sensitive tissues (i.e. most MC receptors are found in secretory organs such as kidney, colon, salivary glands + sweat glands) to stop excessive stimulation of MC Rs.
Synthetic steroids
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
Splitting activities
Modification of natural steroids gives:
Mixed gluco-/ mineralocortiocoid activity
prednisolone, prednisone
Glucocorticoid activity
dexamethasone, betamethasone beclomethasone, budesonide
Mainly mineralocorticoid activity
fludrocortisone
Fludrocortisone used to treat adrenal insufficiency (e.g. Addison’s disease)
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
In this example, S is a steroid drug. 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 R.A.
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.)
N.B. Cytokines stimulate inflamm cells such as fibroblasts/ osteoclasts + protease inhibitors reduce the destruction of extracellular matrix/ collagen.
Unwanted effects of oral corticosteroids
Buffalo hump Cushingold features: Moon face Increased abdominal fat Thinning of the skin Increased risk of infection Porr wound healing Osteoporosis Muscle wasting Hypertension
Metabolic effects – increased availability of glucose/ fats (see Cushing figure), risk of infection (discussed earlier)
Methods of reducing side effects
Lower plasma concentrations → fewer side effects
Choose route of admin to achieve this (e.g. topical admin.)
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
Patients on long-term therapy are advised to carry a card stating the nature of their therapy and the risk of terminating it.
i.e. Cause suppression of normal steroid synthesis
due to excessive negative feedback
may precipitate acute adrenal failure
if exogenous steroids withdrawn abruptly, gradual reduction needed
Patients should carry steroid card
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
Free radicals – rel by neutrophils to kill bacteria, but also damage surrounding tissue; Leukopenia – red wbcs.
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 –shown to reduce IL-1 induced fibroblast proliferation, thereby reducing pannus formation - this is the abnormal growth of fibrous tissue over the joint surface (which leads to a breakdown of bone and cartilage)
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
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
Anticytokine Drugs (contd)
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
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 * May limit use in some patients!
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 – impact of this?
i.e. 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). Impact of bone marrow suppression?
Methotrexate
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
Methotrexate – quicker acting than other drugs.
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)
Immunosuppressants: general problems
Glucocorticoids + other IS drugs:
Increase risk of infection
Increase risk of cancer
