Immunosuppresants + Antirheumatoid Flashcards by Minhee Kim

What are the treatment goals of rheumatoid arthritis

Early use of DMARDs
Use of combination of drugs
Avoid long term use of corticosteroids

How well did you know this?

Not at all

Perfectly

What are DMARDs

What is their role in RA management

Disease modifying anti rheumatic drugs

Prevent disease progression by inhibiting chronic inflammation

How well did you know this?

Not at all

Perfectly

What are the types of DMARDs used

Methotrexate
Sulfasalazine
Leflunomide
Hydroxychloroquine

How well did you know this?

Not at all

Perfectly

What are indications of methotrexate

RA: agent of choice
Chemotherapy (it is a cancer drug)
Psoriasis
IBD

How well did you know this?

Not at all

Perfectly

What is the mechanism of action of methotrexate for cancer treatment

Inhibit dihydrofolate reductase
Inhibit purine and pyrimidine synthesis
Inhibit DNA synthesis
Cytotoxic to rapidly dividing cells

How well did you know this?

Not at all

Perfectly

What is the mechanism of action of methotrexate for non-chemotherapy use

Inhibit other enzymes of purine metabolism
Adenosine accumulates
Adenosine binds to gp GPCR on inflammatory cells
Inhibit T cell activation
Suppress intercellular adhesion molecule expression by T cells

How well did you know this?

Not at all

Perfectly

What are PK properties of methotrexate

Oral bioavailability 33%
IM bioavailability 76%
Admin: oral, IM, SC
High protein binding 50%
Hepatic metabolism 
Renal excretion 
Long T1/2
WEEKLY dosing

How well did you know this?

Not at all

Perfectly

What are side effects of methotrexate

Mucositis
Myelosupression 
Cirrhosis 
Pneumonitis
Pulmonary fibrosis 
Teratogenicity + abortifacient

How well did you know this?

Not at all

Perfectly

What effect do PK properties have on methotrexate use

Switch to IM admin if poor response with oral
Weekly dosing due to long T1/2
DIs with NSAIDs

How well did you know this?

Not at all

Perfectly

What are the prescribing rules of methotrexate

Weekly dosing
Toxicity monitoring: U+Es, LFT, FBC - Baseline, weekly, then 3monthly
FY1 not licensed to prescribe chemotoxic agents
Folic acid should be co-prescribed
Use contraception during treatment
Avoid pregnancy 3 months after stopping treatment

How well did you know this?

Not at all

Perfectly

What are indications for sulfasalazine

IBD

How well did you know this?

Not at all

Perfectly

What is mechanism of action of sulfasalazine

A prodrug that is broken down in large intestine into 5-ASA (active component) and sulfapyridine
5-ASA inhibits T cell proliferation, IL-2 production, causes T cell apoptosis
Sulfapyridine causes SEs

How well did you know this?

Not at all

Perfectly

What are side effects of sulfasalazine

N+V
Rash
Heinz body anaemia
Megaloblastic anaemia 
Myelosupression
Oligospermia
Pneumonitis
Hepatitis 
Stevens Johnson syndrome

How well did you know this?

Not at all

Perfectly

What are the prescribing rules for sulfasalazine

No toxicity monitoring required:
Safe in pregnancy
Not carcinogenic

How well did you know this?

Not at all

Perfectly

What are the cautions for sulfasalazine

G6PD deficiency: drug can be a trigger for haemolytic anaemia
Aspirin allergy: cross sensitivity

How well did you know this?

Not at all

Perfectly

What biological therapies are used in RA management

TNF inhibitors: infliximab, etanercept

Rituximab

How well did you know this?

Not at all

Perfectly

What are indications for TNF inhibitors

RA: at least 2 DMARDs tried
IBD
Psoriasis

How well did you know this?

Not at all

Perfectly

What is mechanism of action of TNF inhibitors

Monoclonal antibody that blocks TNF alpha
Reduce inflammation - reduce leukocyte recruitment to joint
Reduce angiogenesis - reduced VEGF
Reduce joint destruction - reduced MMP

What are side effects of TNF inhibitors

TB reactivation: TNF alpha released by macrophages for granuloma formation and maintenance of infection

What are prescribing rules for TNF alpha inhibitors

Screen for and treat latent TB before starting treatment

What are indications for rituximab

RA
SLE
Vasculitis

What is mechanism of action of rituximab

Monoclonal antibody that causes B cell depletion

Bind to CD20 and cause B cell apoptosis

What are indications of cyclophosphamide

Lupus nephritis
ANCA vasculitis
Chemotherapy: solid, leukaemia, lymphoma

What is mechanism of action of cyclophosphamide

Inhibit DNA replication by Cross linking DNA

Suppresses rapidly dividing cells, T cells, B cells

What are the PK properties of cyclophosphamide

Prodrug: 4HCP is active metabolite Hepatic metabolism by CYP450 enzymes Renal excretion

What are side effects of cyclophosphamide

Risk of malignancy: bladder, leukaemia, lymphoma Infertility Haemorhagic cystitis

Why do you get haemorrhagic cystitis with cyclophosphamide

Acrolein is a metabolite toxic to bladder epithelium

What are prescribing rules with cyclophosphamide

Monitor FBC and renal function

What is mechanism of action of corticosteroids

Inhibit production of pro-inflammatory cytokines: IL-1, IL-2 Inhibit proliferation of Th1 and Th2 cells By acting on intracellular glucocorticoid receptor to inhibit gene transcription

What are indications for azathioprine

``` Organ transplantation SLE Vasculitis IBD Atopic dermatitis ```

What is mechanism of action of azathioprine

Prodrug metabolised by TPMP enzyme To 6MP then to antimetabolite Inhibits purine synthesis Inhibit DNA synthesis

What are PD properties of azathioprine

TPMP enzyme is polymorphic Low expression causes increased myelosupression risk High expression causes risk of under-treatment

What are prescribing rules for azathioprine

TPMP testing: identify patients prone to azathioprine toxicity Monitor LFT, FBC

What are side effects of azathioprine

``` Myelosupression Neutropenia Pancytopenia Increased risk of infection Increased risk of malignancy Hepatitis Pancreatitis ```

What are indications for calcineurin inhibitors

Transplantation Atopic dermatitis Psoriasis

What are types of calcineurin inhibitors

Ciclosporin | Tacrolimus

What is mechanism of action of calcineurin inhibitors

Inhibit calcineurin by binding to + forming complex with cyclophilin protein Drug-cyclophilin complex binds to calcineurin Calcineurin is a phosphatase in T cells involved in IL-2 synthesis Inhibit IL-2 synthesis (thus Th1 mediated response)

What are side effects of calcineurin inhibitors

``` Nephrotoxicity Hypertension Hepatotoxicity Hyperlipidaemia N+V ```

What are prescribing rules of calcineurin inhibitors

Monitor BP and renal function

What are drug interactions of calcineurin inhibitors

CYP450 inducers/inhibitors

What are indications of mycophenolate mofetil

Transplantation

What is mechanism of action of Mycophenolate mofetil

Prodrug converted to mycophenolic acid MPA inhibits inosine monophosphate dehydrogenase IMD inhibits purine synthesis Selective inhibition of B + T cell proliferation (Sparing of other rapidly dividing cells)

What are side effects of mycophenolate mofetil

``` N+V Peptic ulcers Myelosupression Neutropenia Increased infection risk ```