Lecture 16- Immunosuppressants Flashcards
Disease rheumatologists manage
- Inflammatory arthritis
- Rheumatoid and psoriatic
- Systemic lupus erythematosus (SLE)
- Systemic vasculitis
Systemic lupus erythematosus (SLE)
- Very common
- Mimics many disease – multisystemic nature
- Lungs
- Heart
- Blood
- Skin
- Brain etc
Rheumatoid arthritis
- An autoimmune multi-system disease
- Fairly common: UK prevalence 1%
- Initially localized to synovium
- Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
pathogenesis of RA
There should be a fine balance between pro-inflammatory and anti-inflammatory mediators
- In RA overwhelming effect of pro-inflammatory arm
- IL-1 (fever and malaise) , IL-6 (CRP production by the liver)
- TNF-alpha etc etc
- Metalloproteinases- bone erosion
- T cells- cell mediated immunity
- B cells- antibodies which direct damage
diagnosis of RA
Rheumatoid nodules seen less now as RA is picked up earlier
Treatment goals for RA– via immunosuppressants
- Symptomatic relief
- Prevention of joint destruction
treatment strategy for RA
Treatment strategy- drug induced and maintaining remission
- Early use of disease-modifying drugs (DMARDs)
- Aim to achieve good disease control
- Use of adequate dosages
- Use of combinations of drugs
- Avoidance of long-term corticosteroids
what are disease-modifying antirheumatic drugs (DMARDs)
Disease-modifying antirheumatic drugs (DMARDs) are medicines that are normally prescribed as soon as rheumatoid arthritis (RA) is diagnosed, in order to reduce damage to the joints. Rarely, they can have serious side-effects affecting the blood, liver, or kidneys. DMARDS are usually taken for the rest of your life.
Vasculitis
Vasculitis means inflammation of the blood vessels. Inflammation is your immune system’s natural response to injury or infection.
- Also multisystem e.g. lung, skin, kidney
Treatment goals in SLE & vasculitis – via immunosuppressants
- Symptomatic relief e.g arthralgia (pain in joint), Raynaud’s phenomenon
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and by drugs
Immunosuppressants (some are DMARDs)
Cordi Can Make More Angel Cakes, Thanks Love
- Corticosteroids
- Methotrexate
- Azathioprine
- Ciclosporin
- Tacrolimus
- Mycophenolate mofetil
- Leflunomide
- Cyclophosphamide
Other disease-modifying anti-rheumatic drugs (DMARDs)
Non-biologics
- Sulphasalazine
- Hydroxychloroquine
Biologics
- Anti-TNF agents
- Rituximab
- IL-6 inhibitors, JAK inhibitors
general MOA of corticosteroids
- Prevent interleukin IL-1 and IL-6 production by macrophages
- Inhibit all stages of T-cell activation
Transplantation drugs timeline
Azathioprine is an immunosuppressant used to treat
- SLE
- Vasculitis
- Atopic dermatitis
- Bullous skin disease
- IBD e.g. crohns and acute UC
- Weak evidence for RA
azarthiprine is known as a
Steroid ‘sparing’ drug
Used to wean pts off long term steroids use (steroid ADR- Cataracts, thin skin, osteoporosis, CVS effects)
Pharmacodynamics of azathiprine
- First metabolic step that azathioprine undergoes is conversion to 6-mercaptopurine (6-MP)- an immunosuppressant prodrug
- 6-MP is metabolised by Thiopurine S-methyltransferase (TPMT)
- TPMT gene is highly polymorphic
- Low/absent TPMT levels= risk of myelosuppression
- Therefore test for TPMT activity required before prescribing
MOA of azathioprine
- Azathiprine is cleaved to 6-MP
- 6-MP is metabolised by TPMT to various molecules e.g. TIMP
- TIMP further metapolises to 6-MeMPN (antimetabolite)
- which inhibits purine synthesis
- DNA and RNA need purines to be made
Adverse drug response: Azathioprine (all immunosuppressants have these adverse effects)
- Bone marrow suppression (monitor FBC)- myelosuppression
- Increased risk of malignancy
- Esp in transplanted pts
- Increased risk of infections
- Hepatitis
- Monitor LFT
name 2 drugs which come under the class calcineurin inhibitors (another type of immunosuppressant)
: ciclosporin and tacrolimus
uses of calcineurin inhibitors e.g. ciclopsin and tacrolimus
- Transplantation
- Atopic dermatitis and psoriasis
- Not often used in rheumatology
Mode of action of calcineurin inhibitors
- Active against helper T-cells, preventing production against IL-2 via calcineurin inhibition
- Calcineurin exerts phosphatase activity of activates T cells then nucleus factor migration to start IL-2 transcription
- Drug/protein complexes bind calcineurin
- Ciclosporin binds to cyclophilin protein
- Tacrolimus binds to tacrolimus-binding protein
Adverse drug response calcineurin inhibitors
- Renal toxicity
- Gum hypertrophy (ciclosporin)
Contraindication calcineurin inhibitors
Renal problems
Drug-drug interactions calcineurin inhibitors
Multiple due to cytochrome P450
Mycophenolate mofetil comes under the class
immunosuppressant
Mycophenolate mofetil uses
- Primarily in transplantation
- Good efficacy as induction and maintenance therapy for lupus nephritis/vasculitis maintenance
Mode of action Mycophenolate mofetil
- Prodrug derived from fungus penicillium stoloniferum
- Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
- Impairs B and T cell proliferation
- Spares other rapidly dividing cells (due to guanosine salvage pathways in other cells)
Adverse drug response MM
*
- GI: nausea, vomiting, diarrhoea
- Myelosuppression (bone marrow failure)
Contraindication (MM)
Pregnancy
name a drug under the class alkylatong agents used to treat various cancers
Cyclophosphamide
Cyclophosphamide uses
- Lupus nephritis
- Lymphoma, leukaemia, solid cancer
- Wegener’s granulomatosis (ANCA-vasculitis)
Pharmacodynamics of cyclophosphamide
- Prodrug
- Converted in the liver (cytochrome P450) to active forms
- Main metabolite is 4-hydroxycyclophosphamide
- 4-hydroxycyclophosphamide exists in equilibrium with its tautomer, aldophosphamide
- Most of the aldophosphamide is oxidised to make carboxyphosphamide
- Small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)
- Carboxyphosphamide excreted in the kidneys
- Acrolein (another metabolite of cyclophosphamide) is toxic to the bladder epithelium and can lead to haemorrhagic cystitis
- This can be prevented through the use of aggressive hydration and/or Mesna
Mode of action of cyclophosphamide
*
- Cytotoxic agent- alkylating agent- cross links DNA so that it cannot replicate
- Suppresses T and B cell activity
Adverse drug response cyclophosphamide
- Increased risk of bladder cancer, lymphoma and leukaemia
- Infertility: risk relates to cumulative disease and pt age
Contraindication cyclophosphamide
Adjust dose in renal impairment
methotrexate is an
antimetabolite
drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis
uses of methotrexate
- Malignancy e.g. ALL
- Gold standard treatment for early stage RA
- Psoriasis
- Crohn’s disease
- Unlicenced roles: inflammatory myopathies, vasculitis, steroid sparing agent in asthma
Well tolerated, improves QOL, stops retardation of joint damage, anchor drug for DMARD combinations
Pharmacokinetics methotrexate
- Mean oral bioavailability is 33% (13-76%)
- Mean intramuscular bioavailability is 76%
- Administered PO, IM or S/C
- In patients taking PO with partial response or with nausea then swap to s/c
- WEEKLY NOT DAILY DOSING (never dose methotrexate daily everrrr), metabolized to polyglutamates with long half lives (30hours)
- 50% protein bound -NSAIDs displace
- Renal excretion
what to remember with methotrexate
- WEEKLY NOT DAILY DOSING (never dose methotrexate daily everrrr), metabolized to polyglutamates with long half lives (30hours)
methotrexate :Mode of action for cancer
- Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)
- Affinity of methotrexate for DHFR is 1000x that of folate for DHFR
- Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one carbon unit in purine and thymidine synthesis- therefore anti-folate therapy
- Therefore inhibits synthesis of DNA , RNA and proteins
- Acts in the S phase of the cell cycle (DNA and RNA synthesis)–> greater toxic effect on rapidly dividing cells which replicate their DNA more frequently
methotrexate :Non-malignant mode of action
- Mechanisms is not via anti-folate action
- Mechanism unclear
Adverse drug response methotrexate
- Mucositis (respond to folic acid)
- Myelosuppression (respond to folic acid)
- Hepatitis
- Pneumonitis
- Infection risk
Contraindication methotrexate
Pregnancy (teratogenic and abortifacient)
‘Biologics’- novel therapeutics
- Extracted from living systems e.g. whole blood + blood components, stem cell therapy
- Recombinant DNA technology producing substances that are (nearly) identical to the body’s own key signalling proteins e.g. growth hormone, erythropoietin
- Monoclonal antibodies “custom-designed“ made specifically to block any given substance in the body, or to target any specific cell type
- Receptor constructs (fusion proteins), usually based on a naturally- occurring receptor, acting to block it
name a drug under the class anti-TNFa
adalimumab (humira) , infliximab
uses of anti-TNFa
TNF inhibitors are drugs that help stop inflammation. They’re used to treat diseases like rheumatoid arthritis (RA), juvenile arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, ulcerative colitis (UC), and Crohn’s disease
Mode of action TNfa
- Block TNF-a, therefore redcuing
- Inflammation and Cytokine cascade
- Recruitment of leukocytes to joint
- elaboration of adhesion molecules
- production of chemokines
- Angiogenesis and VEGF levels
- Joint destruction, MMPs and other destructive enzymes, bone resorption and erosion
- Decrease cartilage breakdown
adverse drug response Anti-TNFa
- TB reactivation is a risk
- TNFa released by macrophages in response to M TB infection
- TNFa is essential for development and maintenance of granulomata
- Need to screen for latent TB before anti-TNF treatment
contraindications anti-TNFa
- Pregnancy
rituximab is a
biologic which depletes b cells
uses of rituximab
- RA
- Good safety data
mode of action rituximab
- Binds to a unique cell-surface marker CD20 which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or other types
- Causes B cell apoptosis
- B cells
- Present antigens to T cells
- Produce cytokines
- Produce antibodies
- therefore B cell activity reduced
Adverse drug response: rituximab
- GI: nausea, vomiting, diarrhoea
- Myelosuppression (bone marrow failure)
