immune mediated toxicity Flashcards
types of drug hypersensitivity reactions (DHR)
1) immune (allergy)
- immediate: IgE mediated (Atopy)
- delayed: IgM, IgG, T cell mediated
2) nonimmune
- pseudoallergy
what is drug allergy
immunologically mediated hypersensitivity reaction
- immune system response -> host tissue damage -> organ specific/generalised systemic reaction
type of hypersensitivity reaction - type I (immediate)
1) pathologic immune mechanism
- TH2, IgE, mast cell, eosinophil
2) mechanism of tissue injury
- mast cell derived mediators
- cytokine-mediated inflammation
type of hypersensitivity reaction - type II (Ab mediated)
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
type of hypersensitivity reaction - type III (immune complex-mediated)
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
type of hypersensitivity reaction - type IV (T cell mediated diseases)
1) pathologic immune mechanism
- CD4 T cell, CD8 CTL
2) mechanism of tissue injury
- macrophage activation/direct target cell lysis, cytokine mediated inflammation
clinical manifestations of anaphylaxis
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
Serious cutaneous adverse reaction (SCAR)
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
treatment of anaphylaxis
- 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
treatment of SCAR
- similar to burn pt
- supportive care
- IV immunoglobulin & cyclosporin if possible
systemic lupus erythematous (SLE) - general
- auto-immune antibody production
- innate & adaptive immune system disorder
- multisystem disease
- prevalence (non white > white, african highest)
systemic lupus erythematous (SLE) - risk factors
1) genetic disposition
2) environmental
- smoking, infection, certain drugs
- UV light, epstein-barr virus implicated
- pollution
systemic lupus erythematous (SLE) - pathophysiology
- 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
systemic lupus erythematous (SLE) - treatment targets
B cell, plasma cell, B-T cell stimulation, IFN or receptor kinase, cytokines, receptors
systemic lupus erythematous (SLE) - clinical presentation
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
systemic lupus erythematous (SLE) - lab values
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)
systemic lupus erythematous (SLE) - general treatment
- lower disease activity
- slow progression, improve QoL, prevent complication while minimising AE
- treat other comorbidities
systemic lupus erythematous (SLE) - pharmaco list
1) hydroxychloroquine (1st line)
2) NSAID
3) steroids
4) biologic
5) immunosuppressant
systemic lupus erythematous (SLE) - hydroxychloroquine - MOA
- 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
systemic lupus erythematous (SLE) - hydroxychloroquine - indication
prevent flare, improve long term survival, anti-inflam, immunomodulatory, anti thrombotic effect
systemic lupus erythematous (SLE) - hydroxychloroquine - AE
- minimal
- possible retinal tox after 20 yrs of use (need eye exam)
systemic lupus erythematous (SLE) - NSAIDs
- 1st line for acute
- possible worsen lupus nephritis, increase cardiac risk , GI bleed
systemic lupus erythematous (SLE) - steroids
- glucocorticoid
- control flare & maintain low disease activity
- X for pregnant
- AE: osteoporosis, hyperglycaemia, skin atrophy (topical)
systemic lupus erythematous (SLE) - biologics
target & disrupt functioning B cells
systemic lupus erythematous (SLE) - immunosuppressants
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
systemic lupus erythematous (SLE) - nonpharmaco
- sun protection
- exercise, X smoking
drug induced lupus
- type of drugs
1) procainamide, hydralazine, quinidine
2) TNF-alpha inhibitors
- treatment: stop drug.
antiphospholipid syndrome (APS)
- antiphospholipid antibodies produced
- higher risk of thrombosis, clotting, pregnancy morbidity
- treatment
1) primary: aspirin
2) secondary: warfarin
3) hydroxychloroquine: protective
systemic lupus erythematous (SLE) - monitor treatment outcome
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
immunosuppression - indication
1) autoimmune condition
2) solid organ transplant
3) Stem cell/bone marrow transplant
immunosuppression - induction - why?
1) stop damage/worsening of disease
2) prevent body from rejecting
immunosuppression - induction - how?
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
immunosuppression - maintenance - MOA
target T cell activation internally
immunosuppression - maintenance - types
1) calcineurin inhibitor: cyclosporin, tacrolimus
2) antimetabolite: mycophenolate
3) corticosteroid
4) mTOR inhibitor
5) biologics
immunosuppression - approach to transplant therapy
1) pt selection: HLA & blood type
2) intensive induction to avoid rejection
3) multiple maintenance to target different mechanism
- calcineurin inhibitor + glucocorticoid + mycophenolate
immunosuppression - complications
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
immunosuppression - steroids
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
