IC9 Immune Mediated Toxicities Flashcards
what is drug allergy
response of immune system to the antigenic substance leading to host tissue or organ damaged or generalised systemic reaction
(immunological mediated)
2 types of DHR
- immune (allergy): Type I to IV
- immediate (IgE mediated)
- delayed (IgM, IgG, T cell mediated
- non-immune: pseudoallergy
types of ADR
type A: pharmacology mediated, predictable
type B: drug hypersensitivity rx (DHR)
classifications of allergic reactions
Type I: IgE mediated (immediate)
Type II: IgM, IgG antibodies (delayed)
Type III: immune complexes
Type IV: CD4 and CD8 Tcells
most common drug hypersensitivity reaction is
pseudoallergy
define pseudoallergy from drugs
drugs cause the release of mediators (histamines, PGs, kinins) from mast cells and basophil without IgE involvement
3 examples of drugs causing pseudoallergy and the symptoms (MOA)
- vancomycin: red man syndrome (direct release of histamines from mast cells)
- ACEi/ sacubitril: angioedema (inhibit bradykinin breakdown -> vasodilation and increased vascular permeability -> edema and inflammation)
- NSAIDs: NSAIDs induced asthma (alter metabolism of PGs)
effectors of drug hypersensitivity rx
- innate and adaptive immune systems (cellular and humoral components - IgE)
- active chemical mediators (histamine, PAF, PG, thromboxanes, leukotrienes)
how does the complement system cause drug hypersensitivity rx?
complement system (cascade of proteins) activate mast cells and inflammatory mediators
how does PAF cause DHR (eg)
PAF trigger platelet aggregation and clots
(hypersensitivty rx to heparin)
how does PGs/LT (leukotrienes) cause DHR
play a role in broncho regulation (can be dilators or constrictors)
which cellular component is responsible for immediate hypersensitivity rx
mast cells -> release histamines
effects of histamines
vasodilation (swelling, hypotension), vessel permeability, bronchial smooth muscles contraction (SOB)
cellular component involved in delayed hypersensitivity
basophil, eosinophil, neutrophils
define anaphylaxis (drugs that commonly cause it)
acute, life threatening rx that involves multiple systems
(penicillins, NSAIDs, insulins)
when is the risk of fatal anaphylaxis the greatest?
within the first few hours
signs of anaphylaxis
CV: chest pain, low BP, rapid HR
airway: chest tightness, wheezing, SOB
skin: hives, itch, swelling of face
CNS: headache, confusion
GI tract: N/V/D
5 clinical manifestation of DHR
(examples of drugs causing them)
- serum sickness/ drug fever (drug + ab form immune complexes -> systemic sx like fever, rash) eg antibiotics
- drug induced autoimmunity - eg SLE, hemolytic anemia with methyldopa, hepatits with phenytoin)
- vasculitis (inflammation and necrosis of blood vessel walls in skin or organs) - eg allopurinol, thiazide
- respiratory (astham with NSAIDs, chronic fibrotic pulmonary rx with bleomycin/ nitrofurantoin)
- hematologic (eosinophilia, hemolytic anemia, thrombocytopenia, agranulocytosis)
what are the conditions in SCAR
(serious cutaenous adverse reaction)
DRESS (drug rash with eosinophilia and systemic symptoms)
SJS (Stevens-Johnson syndrome)
TEN (toxic epidermal necrolysis)
define DRESS (drug rash with eosinophilia and systemic symptoms)
- eg of drugs
triad of rash, eosinophilia and internal orgain involvement (adenopathy, liver, kidney, lungs, heart)
- eg allopurinol, antoconvulsants
adenopathy: swelling of glands more than 2cm
define SJS/TEN
- differentiate SJS from TEN
- eg of drugs
- mortality rates
- Progressive bullous or “blistering” disorders that constitute dermatologic emergencies (initial stages on skin)
- Progress to mucous membrane erosion and skin detachment
- SJS: less than 10% detachment of skin
- TEN: more than 30% (more serious)
- causes: abx (esp sulfonamides like bactrim)
is drug allergies/ hypersensitivity affected by genetics
yes, genetically determined HLA alleles increase susceptibility to drug hypersensitivity
- genetic factors can influence metabolic deactivation of drugs via phase 1 and 2 metabolism
tx for anaphylaxis
- aim
- drug of choice
- other methods/ drugs
- aim: to restore respiratory and CV function
- epinephrine (adrenaline) counteracts bronchoconstriciton and vasodilation
Others:
- IV fluids to restore volume/BP
- intubation to open airways
- norepinephrine (noradrenaline) if shock
- steroids: to prevent relapse
- glucagon: given when pt on beta blockers to increase HR and contractions (achieve regular HR)
- anithistamines H1 (diphenhydramine), H2 (famotidine, ranitidine)
tx for SCAR
- steriods?
- other drugs?
- no cure (stop drug + symptom control)
- supportive care: wound care to prevent infection, nutritional support, fluids, pain management, prevent infection
- steroids use: controversial
- cyclosporin > IVIG (IV imunoglobulin) for mortality
what increases the risk of developing autoimmune disorder?
genetic background + environmental stimuli (smoking and infection)
aetiology of autoimmune disease
multifactorial
1. cumulative effect of multiple minor genetic variants (each incapable of causing autoimmune disease)
2. environmental factors
drugs target for autoimmune diseases
- cytokines
- cells (T and B)
- kinases
why are autoimmune diseases hard to treat?
- most pt do not respond
- drugs are poorly indicated (off label)
- costly drugs
- pt less likely to seek help
example of non organ specific autoimmune disease
systemic lupus erythematous (SLE) - immune complex can go around the body
define systemic lupus erythematous (SLE)
autoimmune disease associated with auto-antibody production -> form immune complexes that can travel around the body
- RF: females, non-white (african)
- strong genetic disposition (eg family hx) + genetic factors (UV light, infection)
pathophysiology of SLE
SLE autoantibodies cause apoptosis of plasma cells in SLE -> release nucleic acid -> form immune complexes with autoantibodies -> deposition within tissues -> trigger compliment activation and diseases
- number of plasma cells in active SLE is increased (contains autoantibodies)
- T and B lymphocyte activation are altered -> abnormal clearance of apoptotic debris
can SLE be asymptomatic?
yes, autoantibodies can be present for many years before SLE is clinically apparent
tx targets for SLE
B-cell, plasma cell, B-T cell stimulation, IFN or
receptors, kinases, cytokines or receptors
clinical presentation of SLE
- rash - can have activation and remission
- skin disease
- rheumatoid arthritis
- neurological disease
- serositis (inflammation of serous membrane eg pericarditis, pleurisy, peritoneum)
- fever
which clinical presentation of SLE warrants tx?
- lupus nephritis: have different stages, SLE cause kidney death, cure: transplant
- neuropsychiatric lupus: eg stroke, anxiety, seizures
- cardiovascular: pericarditis, myocarditis, atherosclerosis
Clinical presentation of SLE (FBC and immunologic)
FBC
- hemolytic anemia (decr RBC)
- decr WBC/ lymphocytes - more plasma cells
aka differentiated B cells (due to apoptosis)
- dec platelet
Immunologic
- low complement (complements are used up)
- nucleic acid from apoptosis of cell (ANA, dsDNA, anti-Sm, anti-RNP)
Treatment goals
- remission of disease (unrealistic)
- achieve low disease activity (more realistic)
- prevent flares
- improve QOL
- minimise AE
drugs approved by FDA for SLE
hydroxychloroquine
prednisolone
belimumab
aspirin
who should receive hydroxychloroquine for SLE
- advantages of HCQ
- SE
- how long to have effect
all SLE pts
1. prevent flare
2. improve long term survival
3. minimal SE (but renal toxicity after 20yrs of use)
- 4-8 weeks to have effect
why is NSAIDs used in SLE tx
first line: reduce production of PG
- caution in worsening lupus nephritis (NSAIDs worsen renal function)
why is steroids used in SLE tx
as monotx or adjunctive to control flares
- rapid onset
- concerns with high dose or long term use
why is biologics used for SLE tx
- targets and disrupts fucntion of B cells => Belimumab and
Rituximab (Rit resevere diseases)
why is immunosuppressants used for SLE tx
- egs and when are they used
(steroid sparing immunosuppressants)
- IV/PO cyclophosphamide -> induction therapy
- Mycophenolate -> induction and maintenance therapy
- Azathioprine -> alternative to mycophenolate for maintenance
SLE drugs used for pregnancy
- hydroxycholorquine
- cyclophosphamide (2nd and 3rd trimester) - teratogenic and decr fertility
- azathioprine
- calcineurin inhibitors (cyclosporin, tacrolimus)
SE of drugs used in SLE (5 of them)
see notes
MOA of drug induced lupus
- drugs with highest risk
idiosyncratic rx (genes + environment)
possible MOA: drugs induce an immune response by binding to larger molecules like proteins
- procainamide, hydralazine, qunidine, TNF alpha
primary tx of drug induced lupus
stop drug, consider symptomatic tx with steroids
antiphospholipid syndrome (ASP) in SLE
- what does it cause
- tx
antiphospholipid antobody positive in SLE pt
- high risk of clotting
- high risk of pregnancy mrobidity
tx:
- pri thromoboprophylaxis -> aspirin
- pri thromoboprophylaxis -> warfarin
- hydroxychloroquine is protective
monitoring during tx
- ADR
- development of comorbidities
- measures of disease activity
- regular labs: 1-3 mths, 6-12 mths when stable
- antibodies do not need to be repeated at each visit (do not fluctuate with disease activity)
when will a pt need immunosuppression?
- autoimmune conditions
- solid organ transplants
- stem cell/ bone marrow suppression
targets for immunosuppression
many targets, can inhibit any step in proliferation or activation
which is the target for drugs used for organ transplant immunosuppression
T cells
immunosuppression induction meaning and drug used
high potency, short course tx provided ASAP to reduce existing damage and prevent worsening of autoimmune function
- lymphocyte depleting agents (cause cell lysis)
- antithymocyte globulin + alemtuzumab (off label)
- cause lysis of B and T cells - immune modulators to prevent activation and proliferation of T cells: basiliximab
induction and maintenance drugs used for autoimmune disease
refer to notes
approach to transplant tx
- match HLA and blood types of donor and pt
- use intensive induction therapy to avoid initial rejection (biologics > CNI)
- multiple maintenance agents should be used
- CNI + GC + MMF
- CNI + mTOR (limited use due to increased nephrotoxicity) - reduced dosage or window if toxicity exceed benefit
complications of immunosuppression
- opportunistic infection
- cancer
- bone marrow suppression
- bone marrow suppression (esp metabolites)
- hepatotoxicity (esp metabolites)
- renal toxicity (esp CNI, worse when combined with mTOR)
- HTN, hyperlipidemia, hyperglycemia (esp CNI, CS)
which drugs are susbtrate of CYP3A and p-glycoprotein?
CNI and mTOR
MOA of steroids and SE
suppress the production of inflammatory cytokines and decrease T lymphocytes activation
SE: skeletal muscle weakness, myopathy, HTN, dyslipidemia, hyperperglycemia, PJP pneumonia (>2 mth use of prednisolone), osteoporosis (>3mth high dose CS use)
how does exogenouse CS cause HPA axis suppression
Exogenous glucocorticoids cause decr secretion of CRH (corticotropin releasing hormone) and ACTH (adrenocorticotropic hormone)
- Over time, the whole HPA axis becomes inactive, and will be unable to recover its function quickly if exogenous steroids are
stopped (dont stop CS suddenly) - result: adrenal suppression
- occurs when = to >5mg prednisolone/day >3wks
