Lecture 14 - Immunosupressants Flashcards by Callum Donoher

What conditions do rheumatologists managed?

Disordered immune systems:
Inflammation arthritis
Rheumatoid arthritis
Systemic Lupus Erythematous
System I vasculitis

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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

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What joint is often damaged in rheumatoid arthritis?

Metacarpophalangeal joints

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What are some pro-inflammatory mediators?

IL-1
Il-6
TNF-a
Metalloproteinases

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What are some anti inflammatory mediators?

IL-4
TGF-Beta

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What is the pathogenesis for rheumatoid arthritis?

In balance between anti-inflammatory and pro-inflammatory mediators

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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

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What is the goal of treatment of rheumatoid arthritis?

Symptomatic relief
Prevention of joint destruction

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What do we call rheumatoid arthritis affect kids?

Juvenile Idiopathic arthritis

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What increases the risk of you getting rheumatoid arthritis?

Family history (genetic0

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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

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Why do we want to avoid the use of long term corticosteroids?

Side effects (weight gain, osteoporosis, inc risk of infections)

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What is drug assisted remission?

Disease goes into remission but have to remain on drugs to do so

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What is systemic lupus erythrematous?

Autoimmune condition affecting any organ in the body

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What are. Some symtoms of lupus?

Facial rash
Hair loss
Lung scarring
Kidneys

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What is vasculitis?

Inflammation of any type of blood vessels

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What is the treatment goal for SLE and vasculitis?

Systematic relief
Reducing mortality by preventing organ damage

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What are some immunosuppressant drugs?

Corticosteroids
Methotrexate
Azathioprine
Leflunomide
Cyclophosphamide

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How to corticosteroids work as an immunosuppressant?

Prevents IL-1 and IL-6 production by Macrophages which inhibts T cells and B cell activation

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What is the problem with cortitcosteroids?

They aren’t very targeted in the way that they work

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What are DMARDs?

Disease modifying anti-rheumatic drugs (DMARDs)

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What are the 2 categories of DMARDs?

Non-biologics

Biologics

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What are some examples of non-biologic DMARDs?

Methotrexate, sulphasalazine
Leflunomide
Azathioprine

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What are some biologic DMARDs?

Anti-TNF agents
Rituximab
IL-6 inhibitors
JAK inhibitors

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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

Lecture 14 - Immunosupressants Flashcards

(70 cards)