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immune mediated toxicity Flashcards

1
Q

types of drug hypersensitivity reactions (DHR)

A

1) immune (allergy)

  • immediate: IgE mediated (Atopy)
  • delayed: IgM, IgG, T cell mediated

2) nonimmune

  • pseudoallergy
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2
Q

what is drug allergy

A

immunologically mediated hypersensitivity reaction

  • immune system response -> host tissue damage -> organ specific/generalised systemic reaction
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3
Q

type of hypersensitivity reaction - type I (immediate)

A

1) pathologic immune mechanism

  • TH2, IgE, mast cell, eosinophil

2) mechanism of tissue injury

  • mast cell derived mediators
  • cytokine-mediated inflammation
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4
Q

type of hypersensitivity reaction - type II (Ab mediated)

A

1) pathologic immune mechanism

  • IgM, IgG, Ab against cell surface/extracellular matrix antigen

2) mechanism of tissue injury

  • complement & Fc receptor-mediated recruitment & activation of leukocytes
  • opsonisation & phagocytosis
  • abnormalities in cell function
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5
Q

type of hypersensitivity reaction - type III (immune complex-mediated)

A

1) pathologic immune mechanism

  • immune complexes of circulating antigens & IgM or IgG antibodies deposited in vascular basement membrane

2) mechanism of tissue injury

  • complement & Fc receptor mediated recruitment & activation of leukocytes
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6
Q

type of hypersensitivity reaction - type IV (T cell mediated diseases)

A

1) pathologic immune mechanism

  • CD4 T cell, CD8 CTL

2) mechanism of tissue injury

  • macrophage activation/direct target cell lysis, cytokine mediated inflammation
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7
Q

clinical manifestations of anaphylaxis

A

1) skin: hives, itch, flush, swell
2) Airway: trouble breathing, wheeze, chest tight
3) CVS: hypotension, tachycardia
4) serum sickness/drug fever

  • circulating immune complexes (Ag-Ab) -> systematic symptoms
  • drugs: Abx

5) drug related autoimmunity

  • SLE

6) vasculitis

  • inflammation & necrosis of blood vessel walls
  • limited to skin/multiple organs
  • drugs: allopurinol, thiazide

7) respiratory

  • NSAIDs -> asthma
  • drugs: bleomycin, nitrofurantoin -> acute infiltrative & chronic fibrotic pulmonary reaction

8) haematologic

  • eosinophilia
  • haemolytic anaemia, thrombocytopenia
  • agranulocytosis
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8
Q

Serious cutaneous adverse reaction (SCAR)

A

1) Drug rash w eosinophilia & systemic symptom (DRESS)

  • rash + eosinophilia + internal organ involvement
  • internal organ involvement
    ** adenopathy, hepatitis, pnuemonia, nephritis, carditis
  • common drug: allopurinol, anticonvulsant

2) SJS, toxic epidermal necrolysis (TEN)

  • mucous membrane erosion, epidermal detachment
  • associated w Abx
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9
Q

treatment of anaphylaxis

A
  • goal: restore respi & CV function
  • drug choice: epinephrine
  • if reach ambulance/hospi:
    1) IV fluids to restore volume/BP
    2) intubation to save airway
    3) norepinephrine if shock
    4) steroids, glucagon, diphenhydramine + ranitidine
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10
Q

treatment of SCAR

A
  • similar to burn pt
  • supportive care
  • IV immunoglobulin & cyclosporin if possible
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11
Q

systemic lupus erythematous (SLE) - general

A
  • auto-immune antibody production
  • innate & adaptive immune system disorder
  • multisystem disease
  • prevalence (non white > white, african highest)
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12
Q

systemic lupus erythematous (SLE) - risk factors

A

1) genetic disposition
2) environmental

  • smoking, infection, certain drugs
  • UV light, epstein-barr virus implicated
  • pollution
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13
Q

systemic lupus erythematous (SLE) - pathophysiology

A
  • cell apoptosis -> release cell content (including nucleus particles)
  • impaired clearance of self nucleic acid -> travel anywhere in body
  • SLE form auto antibodies to nucleus particles -> form complexes w nucleic aid debris
  • MHC on APC show T cell the complex -> activate T cell -> Activate B cell -> more auto antibodies -> lupus
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14
Q

systemic lupus erythematous (SLE) - treatment targets

A

B cell, plasma cell, B-T cell stimulation, IFN or receptor kinase, cytokines, receptors

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15
Q

systemic lupus erythematous (SLE) - clinical presentation

A

1) lupus nephritis
2) neuropsychiatric lupus

  • stroke, anxiety, seizure, cognitive dysfunction, confusion, peripheral neuropathy, psychosis

3) cardiovascular

  • pericarditis, myocarditis
  • accelerated atherosclerosis

4) others

  • rheumatoid arthritis, serositis, fever, rash
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16
Q

systemic lupus erythematous (SLE) - lab values

A

1) FBC: decreased RBC, WBC, lymphocytes, PLT
2) immunologic

  • antinuclear antibody (ANA)
  • antidouble-stranded DNA (dsDNA)
  • anti-smith antibody (anti-sm)
  • antinuclear ribonucleoprotein (anti-RNP)
  • low complement (C3, C4, CH50)
17
Q

systemic lupus erythematous (SLE) - general treatment

A
  • lower disease activity
  • slow progression, improve QoL, prevent complication while minimising AE
  • treat other comorbidities
18
Q

systemic lupus erythematous (SLE) - pharmaco list

A

1) hydroxychloroquine (1st line)
2) NSAID
3) steroids
4) biologic
5) immunosuppressant

19
Q

systemic lupus erythematous (SLE) - hydroxychloroquine - MOA

A
  • limit APC -> stop toll like receptors on T cells -> suppress T cell activation -> decrease B cel activation -> lesser auto antibodies produced
  • interfere w cytokine production
20
Q

systemic lupus erythematous (SLE) - hydroxychloroquine - indication

A

prevent flare, improve long term survival, anti-inflam, immunomodulatory, anti thrombotic effect

21
Q

systemic lupus erythematous (SLE) - hydroxychloroquine - AE

A
  • minimal
  • possible retinal tox after 20 yrs of use (need eye exam)
22
Q

systemic lupus erythematous (SLE) - NSAIDs

A
  • 1st line for acute
  • possible worsen lupus nephritis, increase cardiac risk , GI bleed
23
Q

systemic lupus erythematous (SLE) - steroids

A
  • glucocorticoid
  • control flare & maintain low disease activity
  • X for pregnant
  • AE: osteoporosis, hyperglycaemia, skin atrophy (topical)
24
Q

systemic lupus erythematous (SLE) - biologics

A

target & disrupt functioning B cells

25
Q

systemic lupus erythematous (SLE) - immunosuppressants

A

1) IV/PO cyclophosphamide

  • severe organ involvement, induction
  • AE: decrease fertility, teratogenic in 1st trimester, hemorrhagic cystitis, bladder cancer

2) mycophenolate

  • induction & maintenance
  • AE: GI rate limiting use, teratogenic

3) azathioprine

  • alternative to mycophenolate for maintenance
  • AE: TPMT before starting, teratogenic
26
Q

systemic lupus erythematous (SLE) - nonpharmaco

A
  • sun protection
  • exercise, X smoking
27
Q

drug induced lupus

A
  • type of drugs

1) procainamide, hydralazine, quinidine
2) TNF-alpha inhibitors

  • treatment: stop drug.
28
Q

antiphospholipid syndrome (APS)

A
  • antiphospholipid antibodies produced
  • higher risk of thrombosis, clotting, pregnancy morbidity
  • treatment
    1) primary: aspirin
    2) secondary: warfarin
    3) hydroxychloroquine: protective
29
Q

systemic lupus erythematous (SLE) - monitor treatment outcome

A

1) ADR
2) develop comorbidities: kidney function, measure disease activity
3) lab values

  • every 1-3 month within active disease
  • 6-12 month if stable
30
Q

immunosuppression - indication

A

1) autoimmune condition
2) solid organ transplant
3) Stem cell/bone marrow transplant

31
Q

immunosuppression - induction - why?

A

1) stop damage/worsening of disease
2) prevent body from rejecting

32
Q

immunosuppression - induction - how?

A

high potency short course to knock immune system down

1) lymphocyte depleting agent

  • MOA: T/B cell lysis
  • antithymocyte globulin (ATG)
  • alemtuzumab

2) immune modulator

  • prevent activation & proliferation of T cells
33
Q

immunosuppression - maintenance - MOA

A

target T cell activation internally

34
Q

immunosuppression - maintenance - types

A

1) calcineurin inhibitor: cyclosporin, tacrolimus
2) antimetabolite: mycophenolate
3) corticosteroid
4) mTOR inhibitor
5) biologics

35
Q

immunosuppression - approach to transplant therapy

A

1) pt selection: HLA & blood type
2) intensive induction to avoid rejection
3) multiple maintenance to target different mechanism

  • calcineurin inhibitor + glucocorticoid + mycophenolate
36
Q

immunosuppression - complications

A

1) immune related

  • opportunistic infection
  • cancer

2) nonimmune related

  • bone marrow suppression (azathioprine, mycophenolate)
  • hepatotox (mycophenolate, azathioprine)
  • renal tox (cyclosporin, tacrolimus, combine w mTOR inhibitor)

3) HTN, hyperlipidaemia, hyperglycaemia

37
Q

immunosuppression - steroids

A

HPA axis suppression

  • common for chronic corticosteroid therapy
  • corticosteroid negative feedback -> stop body from producing hormones -> shut down HPA axis
  • stop steroid = not producing cortisol
  • slowly taper pt off steroid

endo (8 decks)

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