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Pharmo > Immunosuppression > Flashcards

Immunosuppression Flashcards

1
Q

What are the goals of RA treatment?

A

Symptomatic relief

Prevention of further joint destruction

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2
Q

Describe the strategy for RA treatment.

A 
Early use of disease modifying drugs
Good disease control
Drug combinations
Use of adequate dosage
Avoidance of long-term corticosteroids
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3
Q

What are the treatment goals of Systemic Lupus Erythematosus and Vasculitis?

A

Symptom relief
Decreased mortality
Prevention of organ damage
Decreased long-term morbidity

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4
Q

Name the 4 main types of immunosuppressant drugs

A

Corticosteroids
Azathioprine
Calcineurin Inhibitors
Mycophenolate Mofetil

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5
Q

Describe the action of corticosteroids

A

Prevention of IL-1,6 production by macrophages

Inhibition of all stages of T cell activation

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6
Q

Discuss the ADRs of corticosteroids

A 
Weight gain
Fat redistribution 
Osteoporosis
Glucose intolerance
Increased infection risk
Cataracts
Glaucoma
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7
Q

Describe the mechanism of action of azathioprine

A

Cleaved to 6-MP

Anti-metabolite to decrease DNA and RNA synthesis

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8
Q

What are the uses of azothioprine?

A

Maintenance therapy in SLE and Vasculitis
IBD
Bullous Skin Disease
Atopic Dermatitis - steroid sparing

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9
Q

Describe the pharmacology of Azathioprine

A

6-MP metabolised by TPMT enzyme
TPMT is highly polymorphic
Low TPMT levels causes myelosuppression and should be tested for before prescription is given

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10
Q

What are the ADRs associated with Azathioprine? And how can these be monitored?

A

Bone marrow suppression (FBC)
👆risk of malignancy and infection
Hepatitis (LFTs)

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11
Q

What are the common Calcineurin Inhibitors and by what mechanism do they inhibit calcineurin activity?

A

Ciclosporin (binds to cyclophilin protein)
Tacrolimus (binds to tacrolimus binding protein)
Both drug/protein complexes bind to calcineurin to prevent cellular activity

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12
Q

What is the normal mechanism of calcineurin and what is the overall effect of its inhibition?

A

Calcineurin exerts phosphatase activity on nuclear factor of activated T-cells. This then moves to nucleus to begin IL-2 transcription.
Overall effect is 👇 in IL-2 production by helper T-cells.

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13
Q

When are Calcineurin Inhibitors used in practise? Under what circumstances are they used to treat RA?

A

Transplant medicine
Atopic dermatitis
Psoriasis
Used in RA if patient is cytopenic as ciclosporin has no effect on bone marrow

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14
Q

What are the ADRs with Calcineurin Inhibitors?

A 
Nephrotoxicity (hyperkalaemia)
Hypertension
Hyperlipidaemia
Nausea
Hypertrichosis (gingival hypertrophy)
Hyperuricaemia
Drug interactions with those affecting CYP450.
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15
Q

What is the mechanism of action of Mycophenolate Mofetil?

A

Inhibit inosine monophosphate dehydrogenase
Impair B and T cell proloferation
Spare other rapidly dividing cells

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16
Q

What are the ADRs of mycophenolate mofetil?

A

Nausea
Vomiting
Diarrhoea
Myelosuppression

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17
Q

How is mycophenolate mofetil used in practise?

A

Transplantation.
Induction and maintenance therapy vs lupus nephritis.
Toxicity precipitated by renal and hepatic disease.

18
Q

What are the 5 main classes of DMARDs?

Disease-Modifying Anti Rheumatic Drugs

A 
Cyclophosphamide
Methotrexate
Sulphasalazine and Mesalazine
Anti TNF-α Agents
Rituximab
19
Q

Describe the mechanism of action of cyclophosphamide.

A

Alkylating agent -> cross links DNA to prevent replication

Suppresses B and T cell activity

20
Q

What are the indications of cyclophosphamide therapy?

A

Lymphoma, leukaemia
Lupus nephritis
Wegener’s granulomatosis
Polyarteritis nodosum

21
Q

Describe the pharmacodynamics of cyclophosphamide.

A

Prodrug cleaved in liver to active forms

Main metabolite is 4-hydroxycyclophosphamide

22
Q

Discuss the pharmacokinetics of cyclophosphamide

A

Renal excretion

Metabolite (acrolein) toxic to bladder epithelium which can cause haemorrhagic cystitis

23
Q

Discuss the important considerations in cyclophosphamide treatment

A

👆risk of bladder cancer, leukaemia and lymphoma
Infertility
Monitor FBC
Adjusted in renal impairment

24
Q

What diseases can methotrexate be used for?

A

RA
Cancer
Psoriasis
Crohn’s

25
Q

Discuss the known mechanism of action of methotrexate

A

Competitively and reversibly inhibits dihydrofolate reductase (DHFR).
Affinity to DHFR 1000xfold that of folates
Inhibition of DNA, RNA and protein synthesis
Cytotoxic during S-Phase of cell cycle vs rapidly dividing cells

26
Q

Discuss the more unclear MoA of Methotrexate which is most useful in non-malignancy treatment

A

Not via anti folate action
Inhibition of enzymes in purine metabolism
Inhibition of T cell activation
Suppression of intercellular adhesion molecules by T cells.

27
Q

Discuss the pharmacokinetics of methotrexate

A

33% bioavailability (76% IM)
Weekly dosing as metabolites have high half-lives
Renal excretion
Displacement of NSAIDs

28
Q

How is methotrexate used in practise?

A 
Well tolerated
Long continuation of drug
👆QOL
Retardation of joint damage 
Base for DMARD combinations
29
Q

What are the ADRs of methotrexate?

A 
Mucositis
Marrow suppression
Hepatitis
Pneumonitis
Infection
Teratogenic and abortifacient
30
Q

How is methotrexate monitored?

A

Chest X-Ray

FBC, LFT, U and E, Creatinine (baseline and monthly)

31
Q

Describe the MoA of sulfasalazine and mesalazine

A

Inhibition of T cell proliferation and IL-2 production.
Stimulation of T cell apoptosis.
👇chemotaxis and 👇degranulation of neutrophils.

32
Q

Discuss the pharmacokinetics of sulfasalazine and its implications for it use in practise

A

Salicylate (SASA) - largely unabsorbed, remains in enterohepatic circulation.
Sulfapyridine molecule - absorbed but highly protein bound
Main activity vs IBD

33
Q

What are the ADRs of Sulfasalazine?

A 
Myelosuppression
Hepatitis
Rash
Nausea
Abdo pain
Vomiting
34
Q

How is sulfasalazine and mesalazine used in practise?

A 
Effective
Low toxicity
Blood monitoring not required
Few drug interactions
Not carcinogenic
Safe in pregnancy
35
Q

What is a major disadvantage of anti-TNFα treatment?

A

Expensive!

36
Q

Under what circumstances are anti-TNFα agents prescribed for RA?

A

Only after 2 months trial of methotrexate and another DMARD.
Only given with evidence of clinically active RA.
Treatment withdrawn following adverse event or fails to respond after >6 months.

37
Q

What are the effects of anti TNFα agents?

A

👇 inflammation as TNFα required for cytokine cascade and recruitment of leukocytes to joint.
👇 angiogenesis due to reduced VEGF and IL-8 levels.
👇 joint destruction due to inhibition of MMPs, bone resorption, bone erosion and cartilage breakdown.

38
Q

What are the names of the common anti TNFα agents?

A

Etanercept
Infliximab
Adalimumab

39
Q

What are the ADRs of TNFα agents?

A

👆 risk of infection of skin/soft tissue
TB reactivation
Similar risk of new malignancy as with DMARDs
👆 risk of malignancy recurrence

40
Q

What is the MoA of Rituximab?

A

Binds to CD20 on B cell subset.
Activation of complement mediated B cell lysis.
Initiation of cell-mediated cytotoxicity via macrophages.
Induction of apoptosis.

41
Q

What are the risks involved in Rituximab therapy?

A

Hypogammaglobulinaemia
Infection
Hypersensitivity development
Blocking of immune response

42
Q

Describe the pathogenesis in RA and how this can be measured clinically.

A

Increase in IL-1,6 and TNF-α

Pharmo (9 decks)

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