Lecture 14 - Immunosupressants Flashcards
What conditions do rheumatologists managed?
Disordered immune systems:
Inflammation arthritis
Rheumatoid arthritis
Systemic Lupus Erythematous
System I vasculitis
What is rheumatoid arthritis?
Autoimmune condition
Attacks synovium (covering of the joint)
Inflammation change, proliferation of synovium forming a thickened pannus which leads to cartilage damage
What joint is often damaged in rheumatoid arthritis?
Metacarpophalangeal joints
What are some pro-inflammatory mediators?
IL-1
Il-6
TNF-a
Metalloproteinases
What are some anti inflammatory mediators?
IL-4
TGF-Beta
What is the pathogenesis for rheumatoid arthritis?
In balance between anti-inflammatory and pro-inflammatory mediators
How do we diagnose rheumatoid arthritis??
Clinical diagnosis:
-Stiffness in the morning improving after an hour
-arthritis of >3 joints
-arthritis of hand joints
-symmetrical arthritis
-rheumatoid nodules (advanced)
X-ray changes
Serum rheumatoid factor
What is the goal of treatment of rheumatoid arthritis?
Symptomatic relief
Prevention of joint destruction
What do we call rheumatoid arthritis affect kids?
Juvenile Idiopathic arthritis
What increases the risk of you getting rheumatoid arthritis?
Family history (genetic0
What is the treatment strategy for rheumatoid arthritis?
Early use of disease modifying drugs:
Aim to achieve good disease control
Use correct dosages and combos
Why do we want to avoid the use of long term corticosteroids?
Side effects (weight gain, osteoporosis, inc risk of infections)
What is drug assisted remission?
Disease goes into remission but have to remain on drugs to do so
What is systemic lupus erythrematous?
Autoimmune condition affecting any organ in the body
What are. Some symtoms of lupus?
Facial rash
Hair loss
Lung scarring
Kidneys
What is vasculitis?
Inflammation of any type of blood vessels
What is the treatment goal for SLE and vasculitis?
Systematic relief
Reducing mortality by preventing organ damage
What are some immunosuppressant drugs?
Corticosteroids
Methotrexate
Azathioprine
Leflunomide
Cyclophosphamide
How to corticosteroids work as an immunosuppressant?
Prevents IL-1 and IL-6 production by Macrophages which inhibts T cells and B cell activation
What is the problem with cortitcosteroids?
They aren’t very targeted in the way that they work
What are DMARDs?
Disease modifying anti-rheumatic drugs (DMARDs)
What are the 2 categories of DMARDs?
Non-biologics
Biologics
What are some examples of non-biologic DMARDs?
Methotrexate, sulphasalazine
Leflunomide
Azathioprine
What are some biologic DMARDs?
Anti-TNF agents
Rituximab
IL-6 inhibitors
JAK inhibitors
What is Azathioprine used to treat?
SLE and vasculitis as maintenance therapy
Inflammatory bowel disease
Why is Azathioprine considered as a steroid sparing agent?
Azathioprine given once a patient has first been given steroids for their condition and its improved so Azathioprine is given to help keep disease in remission
What dermatological condition is Azathioprine given for?
-Atopic dermatitis
-Bullous skin disease
What is myelosuppression?
Suppression of the bone marrow reducing its ability to produce blood cells
What is the method of action of Azathioprine ?
Azathioprine broken down to 6-MP
6-MP metabolised by TPMT to active metabolite (TIMP)
This then goes into cells and decreases DNA synthesis and RNA synthesis in INFLAMMATORY CELLS
What is the problem with Azathioprine in different individuals?
TMPT gene is highly polymorphic so the activity of TPMT is variable
What does having low levels of TPMT increase the risk of?
Myelosupression
What substance do we need to test the levels of before prescribing Azathioprine?
TPMT
What are the adverse effects of Azathioprine? (Majority of immunosuppressants)
Bone marrow suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis
What are some calcineurin inhibtors?
Cyclosporin
Tacrolimus
What dermatological condition can calcineurin inhibitors be used for?
Atopic dermatitis
Psoriasis
What calcineurin inhibitor is used when a woman want to get pregnant but she has lupus and why?
Tacrolimus
Since it cant cross teh placental barrrier
Why are calcineurin inhibtors not often used?
Causes renal toxicity
Multiple drug interactions (CYP450 interactions)
What are some CYP450 inducers?
Rifampicin
Phenytoin
Omeprazole
Carbamazepine
What are some CYP450 inhibtors?
Ciprofloxacin
Many antifungles
Fluoxetine
Paroxetine
HIV antivirals (Indiavir)
Amiodarone
What is the mechanism of action of cyclosporin and Tacrolimus? (Calcineurin inhbitors)
They inhibit T cells prevention production of IL-2
Cyclosporin binds to cycophilin protein
Tacrolimus bids to Tacrolimus binding protein
What is mycophenolate mofetil ((MMF) used for>?
Transplantations
Good efficacy as induction and maintenance thepay for lupus nephritis/vacuilits maintenance
What is the mechanism of action of mycopphenolate mofetil?
Inhibits IMD (inosine monophosphate dehydrogenase) which impairs B and T cell proliferation (spares other rapidly dividing cells)
What are the side effects of mycophenolate mofetil?
Nausea
Vomiting
Diarrhoea
Myelosupression
What is the the mechanism of action of cyclophosphamide?
Suppressed T cell and B cell activity by cross linking DNA so it can’t replicates
When is cyclophosphamide used?
Its very effective:
Lymphoma, leukaemia, solid cancers
Lupus nephritis
Wegeners granulomatosis
What enzyme converts the prodrug cyclophosphamide into its active form 4-hydroxycyclophosphamide?
CYP450
What is an active metabolite of cyclophamside that is very damaging to the body and causes Haemorrhagic cystitis (bladder bleeding)?
Acrolein
How do we prevent Haemorrhagic cystitis due to acrolein?
Give Mesna with hydration to counteract the effects of acrolein
What toxic effects can cyclophosphamide cause?
Bladder cancer
Lymphoma
Leukaemia
Infertility
Renal damage
What drug is better for lupus nephritis instead of cyclophosphamide in a woman who wants to get pregnant?
Mycophenolate mofetil
What are the uses of methotrexate?
Gold standard treatment of rheumatoid arthritis
Malignancy
Psoriasis
Crohn’s disease
Vasculitis
Steroid sparing drug
What is the mechanism of actioon of methotrexate in malignancy?
Competitive and reversible inhibition of dihdyrofolate reducatse (DHFR)
Stops synthesis of DNA, RNA and proteins since stops Dihdyrofolate REDUCTASE converting dihrydofolate to Tetrahydrofolate which is the key carrier of one-carbon unit is in purine and thymidine synthesis
What stage of the cell cycle does methotrexate act in?
S-phase
What type of cells does methotrexate act the most strongly to?
Rapidly dividing cells (replicate DNA more frequently)
What supplements do we need to give if giving someone methotrexate?
Folic acid
How does methotrexate work in rheumatoid arthritis?
Not sure
Possibly T cell activation prevented
How is methotrexate administer?
Oral
Intramuscular (best way for bioavailability)
Methotrexate very lipophilic
What are the adverse efffects of methotrexate?
Mucositis
Marrow suppression (GIVE FOLIC ACID SUPPLEMNTs)
Hepatitis, cirrhosis
Pneumonia is
Infection risk
TERATOGENIC
ABORTIFACIENT (for ectopic pregnancy)
What is sulfasalazine used for?
Contain aspirin
Rheumatoid arthritis
Rheumatic polyarthiris
Relieve pain stiffness
How does sulfasalazine work?
Inhibits T cell proliferation and IL-2 production
Reduced chemotaxis and degranulation of neutrophil l
Where does suplphasalazine act?
GI issues
Joints
What are the adverse effects of sulfasalazine?
Myelosupression
Hepatitis
Rash
Nausea
Abdopain vomiting
What are the adverse effects of sulfasalazine?
Myelosupression
Hepatitis
Rash
Nausea
Abdopain vomiting
What are biologics?
Extracted from living systems
They are monoclonal antibodies custom to block TNF, IL-6 etc..
What are the effects of biological blocking TNF-a?
Reduced inflammation
Reduced angiogenesis
Reduced joint destruction
Reduced bone resorption
What is the mechanism of action of rituximab?
Binds specifically to CD20 which is found on B cells
What is the function of B cells?
Present antigens to T cells
Produce cytokines
Produce antibodies
What does Rituximab do to B cells?
B cell apoptosis
What condition is rituximab used for?
Rheumatoid arthritis
Lupus
Vasculitis
What are JAK inhibitors (Janus kinase)?
They block loads of receptors
