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Pharmacology > Immunosuppression > Flashcards

Immunosuppression Flashcards

1
Q

Physiologically, what do rheumatoid factors do?

A

Clear old IgGs

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2
Q

What does RA cause?

A

Chronic inflammatory synovitis
Progressive erosion of articular cartilage leading to exposure of bone
Pannus - an inflamed synovium

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3
Q

What’s the problem with an inflamed synovium/pannus?

A

Damages the cartilage by restricting normal nutrient flow and released inflammatory factors

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4
Q

What signs/symptoms are used to diagnose RA?

A 
Morning stiffness for less than 1 hour
Arthritis in 3 or more joints
Symmetrical arthritis
Rheumatoid nodules
Serum rheumatoid factor 
X-ray changes
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5
Q

What are the goals of treatment in RA?

A

Symptomatic relief

Prevent joint destruction

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6
Q

What is the strategy in treatment of RA?

A 
Early use of disease-modifying drugs 
Achieve good disease control
Use adequate dosages 
Use a combination of drugs
Avoid long-term corticosteroids
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7
Q

What is SLE (in one sentence)?

A

An autoimmune connective tissue disease

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8
Q

Symptoms of SLE

A 
Fatigue, malaise, fever, weight loss
Splenomegaly, hepatomegaly, lymphadenopathy
Arthralgia
Oral ulcers
Raynaud's phenomenon
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9
Q

What are symptoms/signs specific to SLE?

A

Erythematous, photosensitive rash seen on the face aka malar rash

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10
Q

What are the aims of treatment in lupus?

A

Symptomatic relief of eg arthralgia, Raynaud’s phenomenon
Reduce mortality - induce remission
Prevent organ damage
Reduce long-term morbidity caused by disease/drugs

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11
Q

What is vasculitis?

A

Inflammation of blood vessels

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12
Q

Symptoms of vasculitis?

A

Arthralgia and lethargy

Skin lesions such as purpura

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13
Q

Treatment goals of vasculitis?

A

Symptom relief
Reduce mortality - induce remission
Prevent organ damage
Reduce long-term morbidity caused by disease/drugs

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14
Q

List some types of immunosuppressants

A 
Corticosteroids
Azathioprine
Ciclosporin
Tacrolimus
Mycophenolate mofetil (MMF)
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15
Q

Name some disease-modifying anti-rheumatic drugs (DMARDs)

A

Methotrexate (first line in RA)
Sulphasalazine (not as strong as MTX)
Anti-TNF agents
Rituximab

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16
Q

Mechanism of action of corticosteroids?

A

Prevent IL-1 and IL-6 production

Inhibit all stages of T-cell activation

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17
Q

Adverse effects of corticosteroids?

A 
Weight gain
Fat redistribution
Striae
Growth retardation 
Osteoporosis
Avascular necrosis
Glucose intolerance
Adverse lipid profile
Infection risk
Cataract formation
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18
Q

What is azathioprine used for?

A

An immunosupressant
Used as maintenance therapy in SLE and vasculitis

Also IBD, bullous skin disease, atopic dermatitis

Steroid-sparing

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19
Q

Mechanism of action of azathioprine?

A

Cleaved to 6 mecaptopurine (6-MP)
Functions as an anti-metabolite to decrease DNA and RNA synthesis by inhibiting purine synthesis
Selectively acts on cells that are highly mitotic

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20
Q

How is azathioprine eliminated?

A

Its active form (6-MP) is eliminated by TPMT

Individuals vary in the level of TPMT activity

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21
Q

What can happen to those who take azathioprine with low TPMT activity? What about high TPMT?

A

Likely to develop myelosuppression and increased risk of infection

High - under-treatment

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22
Q

Adverse effects of azathioprine?

A

Bone marrow suppression
Increased risk of malignancy, especially in transplant patients (as with all immunosuppressants)
Increased risk of infection
Hepatitis

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23
Q

Name the calcineurin inhibitors?

A

Tacrolimus

Cyclosporin

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24
Q

Mechanism of action of calcineurin inhibitors?

A

Prevent the production of IL-2 so active against T-helper cells

  • ciclosporin binds to cyclophilin protein
  • tacrolimus binds to tacrolimus-binding protein

Drug-protein complexes bind to calcineurin, inhibiting it

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25
Q

What does calcineurin normally do?

A

Exerts phosphatase activity on the nuclear factor of activated T-cells
This factor then migrates to the nucleus to start IL-2 transcription

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26
Q

How is ciclosporin produced?

A

By fungus

27
Q

What are calcineurin inhibitors used for?

A

Transplant medicine
Atopic dermatitis and psoriasis
In RA/SLE patients with cytopenias as has no clinical effects on bone marrow

28
Q

How is toxicity monitored with calcineurin-inhibitors?

A

Blood pressure

eGFR

29
Q

Adverse effects of calcineurin inhibitors?

A

Nephrotoxicity leading to hyperkalaemia and hyperuraemia
Hypertension
Hyperlipidaemia
Nausea, vomiting (hyperemesis), diarrhoea
Hypertrichosis
Hyperuricaemia
All the H’s

Has drug interactions due to CYP

30
Q

Mechanism of action of mycophenolate mofetil?

A

Metabolised to mycophenolic acid
Inhibits the enzyme inosine monophosphate dehydrogenase required for guanosine synthesis
Impairs B and T proliferation

31
Q

Why are other rapidly dividing cells spared with MMF?

A

They have guanosine salvage pathways

32
Q

Adverse effects of MMF?

A

Nausea, vomiting, diarrhoea

Myelosuppression

33
Q

What is MMF used for?

A

Transplants
Induction and maintenance therapy for lupus nephritis
Toxicity can be precipitated by both renal and liver disease

34
Q

What causes rheumatoid arthritis?

A

An antibody against IgG called rheumatoid factor mediates it
They bind to form an immune complex
This activates complements and sets of the inflammatory process

Due to an imbalance of pro and anti-inflammatory factors

35
Q

Mechanism of action of cyclophosphamide?

A

It is an alkylating agent - cross-links DNA so that it cannot replicate
Has immunological effects including suppressing B and T cell activity

36
Q

Indications for cyclophosphamide?

A

Lymphoma and leukaemia
Lupus nephritis
Wegener’s granulomatosis (can lead to vasculitis)
Polyarteritis nodosum

37
Q

Absorption and metabolism of cyclophosphamide?

A

Prodrug - converted in the liver by CYP450 to active form

Active metabolite is 4-hydroxycyclophosphamide

38
Q

How is cyclophosphamide excreted?

A

By the kidney

39
Q

What can acrolein, a metabolite of cyclophosphamide do?

A

Toxic to bladder epithelium, can lead to haemorrhage cystitis

Prevented through aggressive hydration/mesna

40
Q

ADRs of cyclophosphamide?

A

Bladder cancer risk
Lymphoma and leukaemia
Infertility - risk relates to cumulative dose and patient age

41
Q

How is cyclophosphamide monitored?

A

FBC

Adjust dose in renal impairment

42
Q

Indications for methotrexate?

A

RA - first line treatment
Malignancy
Psoriasis
Crohn’s

43
Q

Mechanism of action of methotrexate in malignancy?

A

Competitively and irreversible inhibits dihydrofolate reductase
Acts as an antifolate - stops purine and thymidine synthesis so stops DNA, RNA and protein synthesis
Greater effect on rapidly dividing cells

44
Q

Mechanism of action of methotrexate in non-malignant disease?

A

Unknown - suggestions:

  • inhibit enzymes in purine metabolism, causing accumulation of adenosine which is a regulatory autocoid generated in cellular injury/stress, interacts with GPCRs on inflammatory and immune cells to regulate function
  • inhibit T cell activation
  • suppress intercellular adhesin molecule expression by T cells
45
Q

Bioavailability of methotrexate?

A

Oral - 33%

IM - 76%

46
Q

How can MTX be administered?

A

Orally
IM
SC

47
Q

When is methotrexate given? Why?

A

Weekly - has a very long half-life of weeks to months

48
Q

Important DDI with methotrexate?

A

It is 50% protein bound so can be displaced by NSAIDs

49
Q

How is MTX excreted?

A

Renally

50
Q

Adverse effects of MTX?

A

Mucositis
Marrow suppression
-these two respond to folic acid

Hepatitis and cirrhosis
Pneumonitis (hypersensitivity reaction)
Infection risk
Teratogenic and abortifacient

51
Q

How is MTX monitored for toxicity?

A

Baseline CXR

FBC, LFT, U&Es, creatinine (baseline and monthly)

52
Q

Indications for sulfasalazine?

A

RA and IBD

53
Q

What is sulfasalazine made up of?

A

5-aminosalicyclate (5-ASA) and sulfapyridine

54
Q

What is the absorption of sulfasalazine?

A

Travels the length of the upper GI tract where it is poorly absorbed until the colon
In the colon, bacterial action causes the breakdown of sulfasalazine into 5-ASA and sulfapyridine (5-ASA is the active component)

55
Q

How is sulfasalazine thought to treat RA?

A

Inhibit T-cell proliferation and IL-2 production, may cause T-cell apoptosis
Reduce degranulation and chemotaxis of neutrophils

56
Q

ADRs of sulfasalazine?

A

Nashua, fatigue, headache most common
Myelosuppression, hepatitis, allergic rash
Safe in pregnancy

57
Q

Why does sulfasalazine contain the sulphapyridine moiety if this is what is responsible for most ADRs?

A

Allows 5-ASA to get to the colon

58
Q

When is anti-TNF prescribed in RA?

A

After they have trialled methotrexate and one other DMARD

59
Q

Why would anti-TNFs be stopped?

A

If there are any adverse events
If there is failure to respond after 6 months

(Very expensive and bad ADR profile)

60
Q

Name some anti-TNF drugs

A

Infliximab
Etanercept
Adlimumab

61
Q

Mechanism of action of anti-TNF?

A

Blocks TNF-α leading to
-reduced inflammation - affects cytokine cascade, recruits leukocytes to joints leading to elaboration of adhesion molecules and production of chemokines

  • reduced angiogenesis - due to reduced VEGF and IL-8 levels
  • reduced joint destruction - due to less bone resorption and erosion, less MMPs and other destructive enzymes, less cartilage breakdown
62
Q

ADRs of anti-TNF agents?

A

Increased risk of new malignancy in those with prior malignancy
Risk of infection similar to other DMARDs
Increased risk of skin/soft tissue infections
TB reactivation and other intracellular bacterial infections

Rituximab - development of hypogammaglobulinaemia

63
Q

What does rituximab do?

A

Binds specifically to CD20 found on a subset of B cells

  • leads to activation of complement-mediated B cell lysis
  • initiation of cell-mediated cytotoxicity via macrophages
  • induction of apoptosis

Pharmacology (23 decks)

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