PR3152 IC9 Flashcards
Define drug hypersensitivty reactions.
Activation of the immune or inflammtory cells leading to adverse reactions to a drug
What are the two types of hypersensitivity reactions?
Immune
Non immune
What are the types of immune-mediated hypersx reactions?
Immediate: IgE (atopy)
Delayed: IgG, IgM, T cell.
What are non-immune hypersx reactions?
They are pseudoallergies, and usually account for appx 77% of hypersx reactions.
usually from mast cell or basophil derived mediators eg histamine, prostaglandins, kinins AND NOT FROM IgE.
OR
other chemical mediators like platelet activating factor, thromboxanes.
what is a drug allergy?
defined as immunologically mediated hypersensitivity reaction to a drug (antigenic substance) causing host tissue damage and leading to organ-specific or generalised-systemic reaction.
what are type 1 hypersensitivity reactions?
immediate hypersx
igE, Th2, mast cell, eosinophil
1) mast cell derived mediators (vasoactive amines, lipid mediators, cytokines)
and
2) cytokine derived inflammation (eosinophil, neutrophils)
what are type 2 hypersensitivity reactions?
antibody mediated hypersx
igM, igG
complement and Fc receptor mediated recruitment and activation of leukocytes (neutrophils, macrophage)
opsonisation and phagocytosis
what are type 3 hypersensitivity reactions?
immune complex mediated
igG and igM + immune complexes of circulating antigens
what are type 4 hypersensitivity reactions?
t cell mediated
cd4 and cd8
macrophage activation, cytokine mediate inflammation
direct cell lysis by cytokine mediated inflammation
Role of PG in hypersx reactions?
NSAID allergy result in altered metabolism of prostaglandins
(pulmonary smooth muscle contraction)
also involved in platelet aggregation
Prostaglandin source?
mast cell breakdown
synthesis by neutrophils and macrophages
Role of histamine in hypersx reactions?
vasodilation,
bronchial smooth muscle contraction
vessel permeability,
mucus production
itching
sneezing
Histamine source?
mast cell and basophil granules
Role of serotonin in hypersx reactions?
vasodilation
bronchial smooth muscle contraction
serotonin source?
mast cell and basophil granules
Role of protease in hypersx reactions?
mucus production
basement membrane digestion
BP elevation
protease source?
mast cell and basophil granules
Role of platelet activating factors in hypersx reactions?
platelet aggregation and degranulation
pulmonary smooth muscle contraction
source of PAF
PLATELET ACTIVATING FACTORS
mast cell breakdown
eosinophil granules
synthesis by neutrophils, macrophages
source of prostaglandins
mast cell breakdown
synthesis by neutrophils and macrophages.
ROLE of prostaglandins
platelet aggregation,
pulmonary smooth muscle contraction
Role of leukotrienes in hypersx reactions?
vasodilation
increased vessel permeability
bronchial smooth muscle breakdown
mucus production
source of leukotrienes
mast cell membrane breakdown
eosinophil granules
synthesis by neutrophils, macrophages
what are the clinical manifestations of hypersensitivity reactions?
drug fever
hematologic
drug induced autoimmunity
vasculitis
respiratory
what causes drug-induced fevers?
circulating immune complexes causing systemic symptoms like fever, malaise, rash.
antibiotics
what causes/manifestations of drug-induced autoimmunity?
SLE
hematolytic anemia (methyldopa)
hepatitis (phenytoin)
what causes/manifestations of vasculitis
vasculitis caused by the inflammation and necrosis of blood vessel walls.
(allopurinol, thiazide)
what causes/manifestation of respiratory hypersx reactions?
asthma
acute infiltrative and chronic fibrotic pulmonary reactions
(nitrofurantoin, bleomycin)
what causes/manifestation of hematologic hypersx reactions?
eosinophillia (very common)
hemolytic anemia, thrombocytopenia, agranulocytosis.
what are the serious cutaneous allergic reactions (SCAR)
DRESS
- drug rash with eosinophilia and systemic symptoms
SJS and TEN
all can lead to mortality
Explain DRESS and the likely drug causes
usually a triad of eosinophilia, rash, and internal organ involvement
- involving lungs, kidney, etc inflammation
most commonly caused by allopurinol and anticonvulsants
Explain difference between SJS and TEN
TEN detachment rate >30% while SJS is less than <10%
SJS and TEN progression?
bullous/blisters on skin > mucous membrane erosion (involves internal organ also) and epidermal detachment
what are the likely cause of SJS and TEN
sulfonamides e.g., bactrim and sulfonylurea
what is the treatment for severe allergic reactions ie anaphylaxis ?
first line agent:
epinephrine
- counteracts bronchoconstriction, vasodilation
if reach ambulance/hospital:
1) fluids to restore BP/blood vol
2) intubation to save airway (if needed)
3) norepinephrine for shock
4) others:
- steroids = suppress latent reaction
- glucagon = stop inotropic and chronotropic effects to allow heart to beat properly
- diphenhydramine (H1) + ranitidine (H2) = block histamine receptors
what are the risk factors for systemic lupus erythematous?
genetic disposition -> first degree relatives have 20x risk
environment: UV light may alter the structure of the skin and activate SLE
infection: epstein barr virus
drugs
smoking
what is the epidemiology for systemic lupus erythematous?
more frequently occuring in females than males
more frequent in non-whites (esp hispanics) vs whites
description of autoimmune diseases
multifactorial; difficult to treat
genetic disposition and environmental stimuli (smoking, infection) increase risk.
what are examples of autoimmune diseases
organ specifc -> non-organ specific
psoriasis, graves, t1dm, rheumatoid arhtritis, sjogren syndrome, multiple sclerosis, SLE, scloroderma,
what is the pathophysiology for SLE
apoptosis of self -cell releases nucleic acid.
SLE forms complexes with the nucleic acid
impaired clearance of nucleic acid
lymphocyte activation and signalling
activates T cell with presentation of MHC
defective T regulatory cell function
formation and proliferation of B cell auto antibodies.
what is the clinical presentation of SLE
fluctuating symptoms with periods of remission and flares.
typically most present with chronic cutaneous lupus and rheumatoid arthritis
what are the FBC results for a patient with SLE?
low RBC, WBC and platelets due to auto antibodiesw
what are the immunologic tests for a patient with SLE?
ANA (antinuclear)
dsDNA (antidouble-stranded)
anti-sm (anti-smith)
anti-RNP (antinuclear ribonucleoprotein)
low complement C3,C4, CH50)
what are the 4 FDA approved agents for SLE?
hydroxychloroquine
belimumab
aspirin
prednisolone
what are the indications, drug profile of hydroxychloroquine?
hydroxychloroquine recommended in all populations including pregnant women.
minimal adr profile besides retinal toxicity after around 20 years of use.
takes about 4-8 weeks for effects to show.
has anti thrombotic, anti immunomodulatory, and anti-inflammatory properties which reduces the number of flares in the patient.
what are the general 4 classes of agents used for the treatment of SLE
STEROIDS
NSAIDS
IMMUNOSUPPRESSANTS
BIOLOGICS
what is the indication for NSAIDS in SLE treatment
first line agent for acute symptoms
caution in worsening lupus nephritis, increased cardiac risk and GI bleed
what is the indication for STEROIDS in SLE treatment
adjunctive for management of flares
do not use long term, might have long term problems
what is the indication for BIOLOGICS in SLE treatment
consists of belimumab and rituximab
to disrupt B Cell function
what is the indication for IMMUNOSUPPRESSANTS in SLE treatment
THREE TYPES:
IV/PO cyclophosphamide: severe organ involvement, induction therapy
mycophenolate: induction and maintenance therapy
azothiopine: alternative for maintenance therapy.
note that the latter 2 are steroid sparing.
how to classify mild SLE?
1) mild arthritis/constitutional symptoms/rash BSA≤9%
2) PLT 50-100 x 103/mm3
3) SLEDAI ≤6%
4) BILAG C or ≤1 BILAG B
how to classify moderate SLE?
1) RA-like arthritis/cutaneous vasculitis ≤18% /rash 9-18%
2) PLT 20-50 x 103/mm3 / serostitis
3) SLEDAI 7-12%
4) ≥2 BILAG B
how to classify severe SLE?
1) organ involvement (nephritis, cerebritis, mesenteric vasculitis, myelitis, pneumonitis
2) thrombocytopenia PLT < 20x103/mm3
3) SLEDAI >12% or TPP-like disease or acute hemophagocytic syndrome
4) ≥1 BILAG A
how to manage mild SLE?
1st line: HCQ and PO/IM GC
add on refractory: AZA/MTX
how to manage moderate SLE?
1st line: HCQ and PO/IV GC
add on for 1st line: AZA/MTX, MMF, CNI
add on refractory: BEL, MMF, CNI
how to manage severe SLE?
1st line: HCQ and PO/IV GC
add on for 1st line: MMF or CYC
add on refractory: RTX or CYC
what is the remission target for SLE
SLEDAI = 0
HCQ
stop GC
what is the target for low disease activity in SLE
HCQ
GC pred <7.5mg/d
SLEDAI ≤4
immunosuppresives doses stable and well tolerated
what are some non-phx recommendations for SLE?
stop smoking
body weight control
diabetes, CV, lipid control
vaccinations
photo-Resistance
exercise
if antiphospholipid positive, to start on antiplatelets or anticoagulants.
which drugs to avoid in SLE management in pregnant women
AZA/MTX
CYC (avoid in the first trimester)
MMF
caution diabetes for GC in pregnant women
caution ADR preclampsia and HTN
what are some adr for systemic glucocorticoids
eyes:
* glaucoma
* cataract
chronic conditions:
* HTN
* Hyperglycemia
* dyslipidemia
lifestyle:
* fat redistribution
* sleep/mood disturbance
others:
* osteoporosis
* skin atropy
what are some adr for CYC
cystitis
bladder malignancy
infertility
what are some counselling points for mmf
gi side effects which might affect adherence
what are some counselling points for AZA
need to test for TPMT thiopurine methyltransferase before starting
what is the possible MOA causing drug induced lupus
small drug molecules that bind to large molecules like proteins
what are the top 3 drugs causing drug induced lupus
hydralazine
procainamide
quinidine
other drug causes of lupus?
MIMC
minocycline
isoniazide
methyldopa
carbamazepine
TAILS
TNF alpha inhibitor induced lupus like syndrome
what are the antiphospholid antibodies in antiphospholipid syndrome?
ACA: anticardiolipin antibodies
LA: lupus anticoagulants
anti-B2GPI
what are the risks of APA?
high risk of clotting, recall virchow’s triad
high risk of pregnancy morbidity
- if more than 3 unexplained miscarriages, to test for underlying SLE
what are the treatment options for APA? (non preg)
primary thromboprophylaxis: aspirin
secondary: warfarin
HCQ for protective function
what are the treatment options for APA? (preg)
parenteral heparin.
what are the lab paremeters to monitor for SLE and how frequent
1-3 months if active
6-12 months if stable
urinalysis/renal
fbc
lft
complement c3 c4
antidsDNA
CReactive protein
immunosuppression in transplantation (induction therapy)
ASAP high potency and short course
1) immune modulators to prevent proliferation of t cells: basiliximab
2) lymphocyte depleting agents (b and t cell)
- antithymocyte globulin (ATG)
- alemtuzumab
immunosuppression in transplantation (maintenance therapy)
CNI (cyclosporin, tacrolimus)
anti metabolites (mycophenolate, azathioprine)
CSC
mTOR inhibitors (sirolimus, everolimus)
biologics (adalimumab, belatacept)
what is the approach to transplant
1) match HLA to patient blood type
2) initiate high potency induction therapy ASAP to avoid initial rejection
3) maintenance agents (combination therapy)
- encourage use of CNI + CSC + mycophenolate
- avoid CNI + mTOR due to risk of nephro (substrates of cyp450 3a and p glycoprotein)
4) withdraw or reduce if toxic
complications of immune suppression
immune related: infections, cancers
non-immune related:
Bone marrow suppression (esp antimetabolites: azathioprine and mycophenolate)
Hepatotoxicity (esp antimetabolites: Mycophenolate, Azathioprine)
Renal toxicity (esp Cyclosporin, Tacrolimus, worse when combined with mTOR inhibitors)
Hypertension, hyperlipidaemia, hyperglycemia (esp
steroids, calcineurin inhibitors)
immunosuppression maintenance drugs that need TDM
CNI: cyclosporin, tacrolimus
MMF
mTORi: sirolimus, everolimus
what are the long term effects of steroid use
HPA axis suppression causing adrenal insufficiency/suppression
- decrease crh (corticotropin) and acth (adrenocorticotropin)
hypothalamic pituitary adrenal
