immunology therapeutics Flashcards
(170 cards)
1
Q
stages of immunosuppression for SOT
A
1) pre-transplant induction
2) day 0: transplant
3) post-transplant induction and maintenance overlap
4) maintenance
2
Q
SOT maintenance treatment options
A
normal protocols
1) TAC + MMF/EC-MPS + prednisone –> most patients
2) CYA + MMF/EC-MPS + prednisone
minimized protocols
3) low dose TAC + regular dose MMF/EC-MPS
4) low dose CYA + regular dose MMF/EC-MPS
3
Q
how long is a patient on maintenance immunosupression?
A
the lifetime of the organ –> probably their whole life unless the transplanted organ dies
4
Q
induction agent options
A
- ATG (anti-thymocyte globulin) (Thymoglobulin)
- IL-2 receptor blockers (anti-CD25 mAb): basiliximab (Simulect), daclizumab (Zenapax)
- Anti-CD52 mAb: alemtuzumab (Campath)
5
Q
immunosuppression drugs are…
A
narrow therapeutic range drugs
6
Q
immunosuppression drugs have more ___ variability
A
inter-subject –> very extreme!
7
Q
CNIs
A
- tacrolimus
- cyclosporine
8
Q
CNI MoA
A
block calcineurin activation -> prevents NFAT (nuclear factors of activated T cells) transcription factor production -> prevents signal 1 -> prevents further propagation of naïve T cell specification and production –> therefore, fewer immune cells to mount attack on organ
9
Q
immunomodulator
A
agents that can have both positive (inc) and negative (dec) impacts on the immunesystem
10
Q
immunostimulant
A
agents that inc the immune response
11
Q
immunoadjuvants
A
used in combination with antigen administration to enhance that antigen’s immune system impact
- ex: MDP (muramyldipeptide)
12
Q
immunosuppressants
A
agents that can reduce the immune response
- ex: all the drugs we talk about with SOT!
13
Q
biological response modifiers (BRMs)
A
immunomodulators that are endogenous –> CSFs, ILs, IFN, MDP ; are potent immunopharmacology
14
Q
immunopotentiator
A
agent that boosts a failing immune system (an immunostimulant)
- ex: immunoglobulin (antibody)
15
Q
measles definition and presentation
A
*example of artifically acquired active immunity (adaptive immunity)
- respiratory disease caused by virus
- rash, fever, cough, runny nose, Koplik spots (blue-white spots in mouth), tight clusters of red spots, starts at hairline and moved down
- symptoms 10-12 days after exposure, very contangious 4 days before and after rash
- for school, children need MMR vaccine
16
Q
tetanus definition and presentation
A
- aka “lockjaw”
- bacterial infection by Clostridium tetani spores (soil, dust, animal feces)
- spores enter a deep flesh wound -> produce tetanospasmin toxin *not contagious
- muscle spasms start in jaw and progress, fever, sweating, HA, impaired swallowing
- DTap -> Tdap -> Td (every 10 yrs for adult dose)
16
Q
cyclosporine AEs (in order of prevalence)
A
- hyperlipidemia
- nephrotoxicity
- tremor, HA
- HTN
- hyperglycemia, gingival hyperplasia, hirsutism, diarrhea, vomiting
17
Q
tacrolimus AEs (in order of prevalence)
A
- diarrhea, nausea
- nephrotoxicity
- tremor, HA
- insomnia
- hyperglycemia, hyperlipidemia, HTN
18
Q
drugs that inhibit 3A4 and p-gp for CNIs
A
*inc trough, inc AUC
- CCB: verapamil, nicardipine
- antifungals: fluconazole
- antibiotics: clarithromycin, erythromycin
- protease inhibitors: indinavir, ritonavir, boceprevir
- gastric acid suppressors: omeprazole, antacids
- grapefruit juice –> naringin in large amounts
19
Q
drugs that induce 3A4 and p-gp for CNIs
A
*dec trough, dec AUC
- antibiotics: rifampin, nafcillin, rifabutin
- antifungal: caspofungin, terbinafine
- anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- others: octreotide, ticlopidine, orlistat
- herbals: St. John’s wart, Echinacea
20
Q
types of mycophenolic acid
A
- mycophenolate mofetil (MMF)
- mycophenolic acid sodium (MPS)
21
Q
which MPA has less GI AE
A
MPS
22
Q
which MPA is a pro drug
A
MMF
23
Q
which MPA is regular release? delayed release?
A
regular: MMF
delayed: MPS
24
MPA dose comparison
1000mg MMF (prodrug) = 720mg MPS (active) (either the brand or generic)
25
which drugs do you do TDM for?
- CNI !
- MPA - controversial, only use if AEs or monitoring compliance
26
short-acting glucocorticoids
- cortisone (pro-drug)
- hydrocortisone
27
intermediate-acting glucocorticoids
- prednisone (pro-drug)
- prednisolone
- triamcinolone
- methylprednisolone
28
long-acting glucocorticoids
- dexamethasone
- betamethasone
29
equivalent glucocorticoid doses
cortisone: 25mg
hydrocortisone: 20mg
prednisone: 5mg
methylprednisolone: 4mg
dexamethasone: 0.75mg
**potency
30
best glucocorticoid dosing
one AM dose
31
glucocorticoid AEs
(steroids)
- striae
- ecchymoses (bruise really easily)
- avascular necrosis
- cataracts
- changes in behavior, cognition, memory
32
itraconazole DDI with CNIs
inhibit 3A4 and pgp -> inc CNI AUC
33
verapamil DDI with CNIs
inhibit 3A4 and pgp -> inc CNI AUC
34
ritonavir DDI with CNIs
inhibit 3A4 and pgp -> inc CNI AUC
35
phenytoin DDI with CNIs
induce 3A4 and pgp -> dec CNI AUC
36
cyclosporine DDI with MPA
dec EHC -> dec conversion of MPAG to MPA -> dec MPA AUC
37
prednisone AEs
- hyperlipidemia
- hyperglycemia
38
MPA AEs
- vomiting
- diarrhea
- leukopenia
39
thymoglobulin is what type of immunosuppressant?
depleting induction therapy
40
alemtuzumab is what type of immunosuppressant?
depleting induction therapy
41
IL-2 receptor blockers (basiliximab, daclizumab) are what type of immunosuppressant?
non-depleting induction therapy
42
thymoglobulin MoA
polyclonal Ab
block CD2, CD3, CD4, and CD8 -> T cell depletion -> prevent lymphocyte activation and proliferation against allograft
43
after a SOT, a patient is considered...
- immunocompromised
AND
- having secondary immunodeficiency due to immunosuppressive drugs
44
types of cytokines
- pro-inflammatory
- regulatory
- hematopoietic growth factors, colony stimulating factors (CSF)
- interferons
45
1) pro-inflammatory cytokines
- IL-1
- TNF
- CSF
46
2) regulatory cytokines --> up or down regulate immune activity
- interleukins (IL-1, IL-2, IL-4, IL-6, IL-12)
- tumor necrosis factor (TNF-alpha, TNF-beta)
47
3) hematopoietic growth factors or CSFs
- granulocyte CSF (G-CSF)
- granulocyte-monocyte CSF (GM-CSF)
- erythropoietin (RBC CSF)
- IL-3 multi-lineage CSF
48
4) interferon
- IFN-alpha
- IFN-beta
49
interferon
inhibits viral replication, released by our immune cells to protect others
50
IL-1
source: macrophage, fibroblast, endothelial cell
action:
- activate T and B cells
- hematopoietic growth factor
- induce inflammation
51
IL-2
source: CD4+ TH1 cells
action: activate T, B, and NK cells
52
IL-4
source: CD4+ TH2 cells, mast cells, basophils, eosinophils
action:
- B and T cell growth factor
- activate macrophage
- inc IgE
- bone marrow precursor proliferation
53
IL-6
source: CD4+ TH2 cells, macrophages, mast cells, fibroblasts
action:
- B and T cell growth factor
- hematopoietic growth factor
- inc inflammation
54
TNF-alpha
source: macrophages, NK cells, T cells, B cells, mast cells
action:
- activate neutrophils, endothelial cells, lymphocytes, liver cells -> produce acute phase proteins/reactants
55
TNF-beta
source: T cells
action:
- destroy tumor cells
56
IFN-alpha
source: monocytes
action:
- antiviral
- activate NK cells, macrophages
- upregulate MHC I
57
IFN-gamma
source: T cells, NK cells
action:
- activate macrophage, NK cells
- upregulate MHC I and II
58
what is a immunoglobulin
antibody
59
GM-CSF inc
neutrophils AND monocytes
60
G-CSG inc
neutrophils ONLY
61
GM-CSF AE
fever, diarrhea
62
which G-CSF is peglyated
Neulasta --> dec AE
63
functions of endogenous antibodies
- activate complement
- cause opsonization of antigen (in order to digest it)
- directly neutralize virus or toxin
- AB dependent cytotoxicity of cell --> prime antigen and cause destruction (via phagocytosis bc antigen is attached to phagocyte and binds microbe)
- direct antimicrobial action --> generates oxidants
- reduce damage of inflammation for host
64
which immunoglobulin(s) crosses the placenta and therefore protects fetuses?
IgG
65
which immunoglobulins fix complement
IgM, IgG
66
limitations of MoAb
- limited production
- antigenic modulation
- chronic impact on immune system --> can inc infections, cancer
- HAMA reactions
67
primary (congenital) immunodeficiency
genetic defects resulting in impaired maturation or function of immune system components
- ex: severe combined immunodeficiency (SCID)
68
SCID
severe combined immunodeficiency
- defects in T or B cell functions and maturation
a primary immunodeficiency (congenital)
68
SCID
severe combined immunodeficiency
- defects in T or B cell functions and maturation
a primary immunodeficiency (congenital)
68
SCID
severe combined immunodeficiency
- defects in T or B cell functions and maturation
a primary immunodeficiency (congenital)
69
secondary (acquired) immunodeficiency
non-genetic and acquired over lifetime
70
causes of secondary immunodeficiency
developed countries: cancer, anti-neoplastic therapy, irradiation, IMMUNOSUPPRESSION THERAPY
developing countries: environment, malnutrition, advanced age, chronic diseases
71
what are the clinical risks of neutropenia?
inc in opportunistic infections
72
cluster of determination definition
a classification of lymphocytes based on the specific cell surface markers and the number of sites
- use to monitor: AIDS, leukemia, SOT, SLE, bone marrow transplant
73
CD3
all T lymphocytes (helper and cytotoxic)
74
CD4
helper T lymphocytes, either TH1 or TH2
75
CD8
cytotoxic/suppressor T lymphocytes
76
CD20
B lymphocytes
77
CD25
activated T lymphocytes, B lymphocytes, IL-2 receptor chain (Tac)
78
CD56
NK cells
79
deficiency in the immunes system can...
inc infection risk
80
how to measure CELL MEDIATED (T cell) immunocompetency
measure cell mediated immunity and T lymphocytes
*intradermal administration of common recall antigens
81
common recall antigens
- candida albicans
- mumps
- tuberculin (PPD)
- trichophyton
82
cylex immune cell assay
measures suppression of CD4 lymphocytes
83
total immunoglobulins (Ig) measure
measures B cell function via serum protein electrophoresis (SPEP)
- primary or secondary immunodeficiencies
- measures: IgG, IgM, IgG, IgE, IgD
if IgM --> active infection
if IgG --> later/memory Ag, therefore hepatitis
84
complement system measures
humoral response -> AG lysing, opsonization
85
SOT rejection mediated by
T-cells (cell mediated)
86
another name for self-antigens
auto-antigens
87
immunologic tolerance
state in which an individual is incapable of developing an immune response to a specific antigen
**good --> stops us from reacting to all antigens
88
self-tolerance
lack of responsiveness to an individual's own body antigens
**good --> needed to allow us to not attack our own cells and tissues
89
systemic lupus erythematosus presentation and MoA
- autoimmune disorder; autoantibodies against nucleic acid, erythrocytes, coagulation proteins, lymphocytes, platelets
- inc in women, 15-45yrs
- complement activated, AG-AB complexes formed and deposited in organs of vasculature system
- chronic and acute inflammation
- due to reduced suppression of immune system B cells
- butterfly rash
90
discoid lupus erythematosus
severe inflammation, scarring, rashes on face scalp ears --> butterfly rash
91
SLE treatment
belimumab (Benlysta)
- B cell depletion --> balances out the upregulated/overactive B cell production in SLE
92
which cytokine receptor can inc or dec immune activity and is the concept for RA drug therapy
soluble cytokine receptors
93
basic classifications of hypersensitivies
adaptive immunity:
- humoral:
type I: immediate (anaphylactic)
type II: cytotoxic
type III: immune complex mediated
- cell mediated:
type IV: cell mediated
94
allergy
immunologic responses to environmental or endogenous antigens that can result in disease or hypersensitivity and be clinically harmful
95
autoimmunity
disturbance in immunologic tolerance --> initiates a response against auto-antigens
could also say a disturbance with self-tolerance
96
alloimmuntiy
immune system of host mounts immunologic response to tissue of another individual
- transplant, transfusion
97
clinical features of hypersensitives (allergic drug reactions)
- no correlation with pharmacologic properties (not due to the drug's MoA)
- requires an induction period on primary exposure (will not happen on the first interaction with the drug)
- occurs with doses below therapeutic range
- small proportion of population
- disappears when therapy stops, reappears when small doses of structurally similar therapy starts
- may be able to desensitize
98
predisposing factors to hypersensitivity reactions
- female, adult
- Hx of asthma, allergic rhinitis, atopic dermatitis --> may be more severe than other patients
- AIDS, Epstein-Barr, lymphocytic leukemia
- previous allergy to similar drugs
- topical drug administration --> greatest sensitization risk vs oral is least
99
onset of hypersensitivity depends on
- original immunologic insult -> prevention, follow up treatment
- genetics -> predisposition or not
- specific immunologic reaction --> chronic vs acute, any remaining consequences
- host risk factors --> primary immunodeficiency, secondary immunodeficiency
100
immunodeficient patients are more/less at risk for hypersensitivity reactions
more
101
secondary immunodeficiency causes
- immunosuppressive therapy
- irradiation
- chronic diseases: CKD, liver disease, cancer, transplantatio, SLE
- malnutrition
102
components of a detailed drug history
- prior allergic and medication encounters
- nature/severity of reaction
- other medical problems
- temporal relationship between drug and reaction (dose, date, duration, time, treatment)
- prior exposure of same or structurally related medications after reaction
- effect of drug discontinuation --> if it lingered maybe more of a disease than a hypersensitivity
- treatment response
- prior diagnostic testing or re-challeneg
- route of administration
- preservatives or additives in the formulation
103
anaphylaxis presentation
- respiratory depression
- laryngeal edema
- hypotension
- cardiovascular collapse
104
allergen
an immunogen (antigen) that results in an allergic reaction
105
atopic allergies
genetic tendency to develop allergic diseases --> includes atopy
106
atopy
heightened immune responses to common allergens; conditions include:
- asthma and allergic
- food allergies
- specific drugs
- insect venom
107
if penicillin allergy, avoid
carbapenems
108
if aminopenicillin (amoxicillin, ampicillin) allergy, avoid
- cefadroxil
- cephalexin
- cefaclor
- cefprozil
109
if penicillin allergy, can use
aztreonam
110
which drugs can you use desensitization for
penicillin, co-trimoxazole
111
which antibodies mediate type i hypersensitivies
IgE
112
which antibodies mediate type ii and iii hypersensitivies
IgG
113
which hypersensitive can impact the fetus?
ii and iii bc only IgG can cross placenta!
114
symptoms of hemolytic anemia of newborn
- hemolytic anemia (bilirubin inc, jaundice)
- high output HF (death)
- enlarged liver and spleen
- generalized swelling
- impaired platelets (petechial (facial) hemorrhaging)
115
minimal organ involvement
drug induced lupus (iii)
116
elevated ANA titer, SS-DNA, ESR
drug induced lupus (iii)
117
serum sickness
iii
- generalized reaction
- exogenous antigen
118
drug-induced lupus
iii
- endogenous antigen
119
arthus reaction
iii
- localized reaction
120
agents that cause acute serum sickness
- animal serums (polyclonal antibodies)
- bee venom injections
- cefaclor
- ciprofloxacin
- insulin from animal sources
- iron dextran
- IVIG
- MoAB
- penicillins
- sulfonamides
121
causes of anergy
- elderly
- severe debility
- disseminated TB (spread throughout body)
- HIV
- IMMUNOSUPPRESSIVE TREATMENT
- glucocorticoid therapy
- recent viral infection
- immunization
122
anergy
absence of CELL MEDIATED immune response
123
number one cause of SJS or TENS
drugs!
4-12 days after exposure!!!
124
drug causes of SJS or TENS
- sulfa drugs: cotrimoxazole, sulfasalazine
- other antibiotics: aminopenicillins, fluoroquinolone, cephalosporins
- anti-epileptics: phenytoin, carbamazepine, phenobarbital, valproate, lamotrigine
- other drugs: piroxicam, allopurinol
125
SJS
less than 10%
126
TEN
greater than 30%
127
SJS/TEN
15-30%
128
how long does it take for AGEP to develop
3 weeks after exposure
129
most frequent drug causes of AGEP
- aminopenicillins
- sulphonamides
- quinolone
- hydroxychloroquine
- terbinafin
- diltiazem
130
drug induced fever mostly caused by
biologics --> therefore need pre-treatment to prevent!!
131
immunosuppressive drug monitoring
- patient risk factors
- drug PK (exposure, ...)
- graft function
- drug PD (outcomes, AEs)
- pharmacogenomics
132
secondary (acquired) immunodeficiency (SAID)
immune system deficiencies acquired throughout life that are NOT due to genetic/congenital immune disorders
133
SAID risks
- inc typical and opportunistic infection --> more severe
- inc in risk of tumors --> remove immunosurveilance of atypical cells that could become cancers
134
common causes of SAID and mechanism of cause
- HIV infection --> deplete CD4 cells
- irradiation and chemo --> dec bone marrow leukocyte precursors
- IMMUNOSUPPRESION FOR GRAFT REJECTION AND INFLAMMATORY DISEASES --> deplete or functionally impair lymphocytes
- bone marrow cancers --> reduce site of leukocyte development
- protein-calorie malnutrition --> inhibit lymphocyte maturation and function
- spleen removal --> dec phagocytosis of microbes
135
what to check when taking labs for TDM
- compliance
- dose
- exact timing of last dose
**PATIENT CANNOT TAKE MEDS THE MORNING OF GETTING LABS DRAWN --> bc is then a peak not a trough!!!
136
CNI MoA
inhibit calcineurin --> prevent signal 1 --> prevent cell DNA proliferation for replication of T cell
137
MPA MoA
interfere with T cell nucleotide synthesis --> prevent more T and B cells from being committed and proliferating and therefore attacking graft
- anti-proliferative drug
138
post-transplant induction and start of maintenance therapy CNI dosing
AVOID FULL DOSES
- cause renal vasoconstriction and slower function of renal graft --> not good immediately post transplant
139
induction therapy overall strategy/MoA
block T cell, or other immunologic, activation at the time of graft placement
140
induction therapy advantages
- improve early graft function
- prevent graft rejection
- improve graft survival
141
induction therapy disadvantages
- inc cost
- inc risk of cytomegalovirus (CMV)
- inc risk of post-transplantation lymphoproliferative disease (PTLD) --> bc dec immunosurveillance of atypical cells
142
factors affecting CNI PK
- fat content in meals
- time post-transplant --> early post transplant = inc absorption
- type of organ transplant
- compromised GI function --> diarrhea dec absorption
- bioavailability of dosage forms -> generally low
- DDIs
143
which CNI more potent
TAC
144
which CNI more F
CYA
145
which CNI longer half life
TAC
146
IR TAC
Prograf
147
ER TAC
Astagraf XL
Envarsus
148
IV TAC
IV Prograf
149
oral CYA
modified:
Neoral
Gengraf
non-modified:
Sandimmune
150
IV CYA
non-modified:
Sandimmune
151
which MPA is a prodrug
CellCept (MMF)
152
which MPA is regular release
CellCept (MMF)
153
which MPA is enteric coated
Myfortic (EC-MPS)
154
which MPA is delayed release
Myfortic (EC-MPS)
155
MMF:MPS dose ratio
1000mg MMF : 720mg MPS
prodrug : active
156
nephrotoxicity, think
CNI
157
severe GI side effects, think
MPA
158
MPA DDIs that dec MPA AUC due to EHC
- CYA
- cholestyramine, bile and resins
- antibiotics (norfloxacin metronidazole, cipro, augmentin, rifampin)
159
MPA DDIs that inc MPA AUC due to EHC
- TAC
160
factors impacting MPA PK
- time after transplant
- DDIs
- EHC --> concurrent CNI effects
- other disease states --> adjust for renal dosing
- food
- ethnicity
- genetic polymorphisms
161
post transplant complications
post-transplant...
- HTN
- opportunistic infections
- DM
- HLD
- osteoporosis
- lymphoproliferative disorder (dec immunosurveillance)
162
glucocorticoid DDIs: inhibit gluco --> inc AUC
- oral contraceptives
- estorgens
- macrolide antibiotics (erythromycin, clarithromycin)
- ketoconazole
- isonazid
- naproxen
- CYA
163
glucocorticoid DDIs: inc hypoK
- diuretic
- amphotericin B
164
glucocorticoid DDI: induce gluco --> dec AUC
- phenytoin
- phenobarbital
- rifampin
- carbamazepine
- edphedrin
165
glucocorticoid DDI: drugs that gluco induces their metabolism --> dec these drug AUCs
- CYA
- TAC
- MPA
166
glucocorticoid DDIs: dec steroid absorption --> dec AUC of gluco
- cholestyramine
- antacids
167
glucocorticoid AEs
- striae
- ecchymoses
- avascular necrosis
- cushings --> adrenal atrophy
- dyslipidemia
- change in behavior, cognition
- GI bleed, ulcer
- delayed wound healing
- bone necrosis
- cataracts
- glaucoma
- hyperglycemia
- HLD
- child growth suppression
