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PR3152 (cleefy) > PR3152 IC9 > Flashcards

PR3152 IC9 Flashcards

1
Q

Define drug hypersensitivty reactions.

A

Activation of the immune or inflammtory cells leading to adverse reactions to a drug

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2
Q

What are the two types of hypersensitivity reactions?

A

Immune

Non immune

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3
Q

What are the types of immune-mediated hypersx reactions?

A

Immediate: IgE (atopy)
Delayed: IgG, IgM, T cell.

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4
Q

What are non-immune hypersx reactions?

A

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.

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5
Q

what is a drug allergy?

A

defined as immunologically mediated hypersensitivity reaction to a drug (antigenic substance) causing host tissue damage and leading to organ-specific or generalised-systemic reaction.

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6
Q

what are type 1 hypersensitivity reactions?

A

immediate hypersx

igE, Th2, mast cell, eosinophil

1) mast cell derived mediators (vasoactive amines, lipid mediators, cytokines)
and
2) cytokine derived inflammation (eosinophil, neutrophils)

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7
Q

what are type 2 hypersensitivity reactions?

A

antibody mediated hypersx

igM, igG

complement and Fc receptor mediated recruitment and activation of leukocytes (neutrophils, macrophage)

opsonisation and phagocytosis

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8
Q

what are type 3 hypersensitivity reactions?

A

immune complex mediated

igG and igM + immune complexes of circulating antigens

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9
Q

what are type 4 hypersensitivity reactions?

A

t cell mediated

cd4 and cd8

macrophage activation, cytokine mediate inflammation
direct cell lysis by cytokine mediated inflammation

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10
Q

Role of PG in hypersx reactions?

A

NSAID allergy result in altered metabolism of prostaglandins
(pulmonary smooth muscle contraction)

also involved in platelet aggregation

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11
Q

Prostaglandin source?

A

mast cell breakdown

synthesis by neutrophils and macrophages

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12
Q

Role of histamine in hypersx reactions?

A

vasodilation,
bronchial smooth muscle contraction

vessel permeability,

mucus production
itching
sneezing

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13
Q

Histamine source?

A

mast cell and basophil granules

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14
Q

Role of serotonin in hypersx reactions?

A

vasodilation

bronchial smooth muscle contraction

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15
Q

serotonin source?

A

mast cell and basophil granules

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16
Q

Role of protease in hypersx reactions?

A

mucus production
basement membrane digestion
BP elevation

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17
Q

protease source?

A

mast cell and basophil granules

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18
Q

Role of platelet activating factors in hypersx reactions?

A

platelet aggregation and degranulation

pulmonary smooth muscle contraction

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19
Q

source of PAF

PLATELET ACTIVATING FACTORS

A

mast cell breakdown
eosinophil granules
synthesis by neutrophils, macrophages

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20
Q

source of prostaglandins

A

mast cell breakdown
synthesis by neutrophils and macrophages.

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21
Q

ROLE of prostaglandins

A

platelet aggregation,
pulmonary smooth muscle contraction

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22
Q

Role of leukotrienes in hypersx reactions?

A

vasodilation
increased vessel permeability
bronchial smooth muscle breakdown
mucus production

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23
Q

source of leukotrienes

A

mast cell membrane breakdown
eosinophil granules
synthesis by neutrophils, macrophages

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24
Q

what are the clinical manifestations of hypersensitivity reactions?

A

drug fever

hematologic

drug induced autoimmunity

vasculitis

respiratory

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25
Q

what causes drug-induced fevers?

A

circulating immune complexes causing systemic symptoms like fever, malaise, rash.

antibiotics

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26
Q

what causes/manifestations of drug-induced autoimmunity?

A

SLE
hematolytic anemia (methyldopa)
hepatitis (phenytoin)

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27
Q

what causes/manifestations of vasculitis

A

vasculitis caused by the inflammation and necrosis of blood vessel walls.
(allopurinol, thiazide)

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28
Q

what causes/manifestation of respiratory hypersx reactions?

A

asthma

acute infiltrative and chronic fibrotic pulmonary reactions
(nitrofurantoin, bleomycin)

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29
Q

what causes/manifestation of hematologic hypersx reactions?

A

eosinophillia (very common)

hemolytic anemia, thrombocytopenia, agranulocytosis.

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30
Q

what are the serious cutaneous allergic reactions (SCAR)

A

DRESS
- drug rash with eosinophilia and systemic symptoms

SJS and TEN

all can lead to mortality

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31
Q

Explain DRESS and the likely drug causes

A

usually a triad of eosinophilia, rash, and internal organ involvement
- involving lungs, kidney, etc inflammation

most commonly caused by allopurinol and anticonvulsants

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32
Q

Explain difference between SJS and TEN

A

TEN detachment rate >30% while SJS is less than <10%

33
Q

SJS and TEN progression?

A

bullous/blisters on skin > mucous membrane erosion (involves internal organ also) and epidermal detachment

34
Q

what are the likely cause of SJS and TEN

A

sulfonamides e.g., bactrim and sulfonylurea

35
Q

what is the treatment for severe allergic reactions ie anaphylaxis ?

A

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

36
Q

what are the risk factors for systemic lupus erythematous?

A

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

37
Q

what is the epidemiology for systemic lupus erythematous?

A

more frequently occuring in females than males

more frequent in non-whites (esp hispanics) vs whites

38
Q

description of autoimmune diseases

A

multifactorial; difficult to treat

genetic disposition and environmental stimuli (smoking, infection) increase risk.

39
Q

what are examples of autoimmune diseases

A

organ specifc -> non-organ specific

psoriasis, graves, t1dm, rheumatoid arhtritis, sjogren syndrome, multiple sclerosis, SLE, scloroderma,

40
Q

what is the pathophysiology for SLE

A

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.

41
Q

what is the clinical presentation of SLE

A

fluctuating symptoms with periods of remission and flares.

typically most present with chronic cutaneous lupus and rheumatoid arthritis

42
Q

what are the FBC results for a patient with SLE?

A

low RBC, WBC and platelets due to auto antibodiesw

43
Q

what are the immunologic tests for a patient with SLE?

A

ANA (antinuclear)
dsDNA (antidouble-stranded)
anti-sm (anti-smith)
anti-RNP (antinuclear ribonucleoprotein)

low complement C3,C4, CH50)

44
Q

what are the 4 FDA approved agents for SLE?

A

hydroxychloroquine
belimumab
aspirin
prednisolone

45
Q

what are the indications, drug profile of hydroxychloroquine?

A

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.

46
Q

what are the general 4 classes of agents used for the treatment of SLE

A

STEROIDS
NSAIDS
IMMUNOSUPPRESSANTS
BIOLOGICS

47
Q

what is the indication for NSAIDS in SLE treatment

A

first line agent for acute symptoms

caution in worsening lupus nephritis, increased cardiac risk and GI bleed

48
Q

what is the indication for STEROIDS in SLE treatment

A

adjunctive for management of flares

do not use long term, might have long term problems

49
Q

what is the indication for BIOLOGICS in SLE treatment

A

consists of belimumab and rituximab

to disrupt B Cell function

50
Q

what is the indication for IMMUNOSUPPRESSANTS in SLE treatment

A

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.

51
Q

how to classify mild SLE?

A

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

52
Q

how to classify moderate SLE?

A

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

53
Q

how to classify severe SLE?

A

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

54
Q

how to manage mild SLE?

A

1st line: HCQ and PO/IM GC
add on refractory: AZA/MTX

55
Q

how to manage moderate SLE?

A

1st line: HCQ and PO/IV GC
add on for 1st line: AZA/MTX, MMF, CNI
add on refractory: BEL, MMF, CNI

56
Q

how to manage severe SLE?

A

1st line: HCQ and PO/IV GC
add on for 1st line: MMF or CYC
add on refractory: RTX or CYC

57
Q

what is the remission target for SLE

A

SLEDAI = 0
HCQ
stop GC

58
Q

what is the target for low disease activity in SLE

A

HCQ
GC pred <7.5mg/d
SLEDAI ≤4
immunosuppresives doses stable and well tolerated

59
Q

what are some non-phx recommendations for SLE?

A

stop smoking
body weight control
diabetes, CV, lipid control
vaccinations
photo-Resistance
exercise

if antiphospholipid positive, to start on antiplatelets or anticoagulants.

60
Q

which drugs to avoid in SLE management in pregnant women

A

AZA/MTX
CYC (avoid in the first trimester)
MMF

caution diabetes for GC in pregnant women
caution ADR preclampsia and HTN

61
Q

what are some adr for systemic glucocorticoids

A

eyes:
* glaucoma
* cataract

chronic conditions:
* HTN
* Hyperglycemia
* dyslipidemia

lifestyle:
* fat redistribution
* sleep/mood disturbance

others:
* osteoporosis
* skin atropy

62
Q

what are some adr for CYC

A

cystitis
bladder malignancy
infertility

63
Q

what are some counselling points for mmf

A

gi side effects which might affect adherence

64
Q

what are some counselling points for AZA

A

need to test for TPMT thiopurine methyltransferase before starting

65
Q

what is the possible MOA causing drug induced lupus

A

small drug molecules that bind to large molecules like proteins

66
Q

what are the top 3 drugs causing drug induced lupus

A

hydralazine
procainamide
quinidine

67
Q

other drug causes of lupus?

A

MIMC

minocycline
isoniazide
methyldopa
carbamazepine

TAILS
TNF alpha inhibitor induced lupus like syndrome

68
Q

what are the antiphospholid antibodies in antiphospholipid syndrome?

A

ACA: anticardiolipin antibodies
LA: lupus anticoagulants
anti-B2GPI

69
Q

what are the risks of APA?

A

high risk of clotting, recall virchow’s triad
high risk of pregnancy morbidity
- if more than 3 unexplained miscarriages, to test for underlying SLE

70
Q

what are the treatment options for APA? (non preg)

A

primary thromboprophylaxis: aspirin
secondary: warfarin
HCQ for protective function

71
Q

what are the treatment options for APA? (preg)

A

parenteral heparin.

72
Q

what are the lab paremeters to monitor for SLE and how frequent

A

1-3 months if active
6-12 months if stable

urinalysis/renal
fbc
lft
complement c3 c4
antidsDNA
CReactive protein

73
Q

immunosuppression in transplantation (induction therapy)

A

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

74
Q

immunosuppression in transplantation (maintenance therapy)

A

CNI (cyclosporin, tacrolimus)
anti metabolites (mycophenolate, azathioprine)
CSC
mTOR inhibitors (sirolimus, everolimus)
biologics (adalimumab, belatacept)

75
Q

what is the approach to transplant

A

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

76
Q

complications of immune suppression

A

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)

77
Q

immunosuppression maintenance drugs that need TDM

A

CNI: cyclosporin, tacrolimus
MMF
mTORi: sirolimus, everolimus

78
Q

what are the long term effects of steroid use

A

HPA axis suppression causing adrenal insufficiency/suppression
- decrease crh (corticotropin) and acth (adrenocorticotropin)

hypothalamic pituitary adrenal

PR3152 (cleefy) (13 decks)

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