Transplant Drugs & HIV Antiretrovirals Flashcards
organ rejection that happens within days due to reactivation of sensitized T cells
accelerated
refers to organ rejection that develops over days to weeks in association with primary activation of T cells in response to antigens expressed on the surface of allograft cells and/or on antigen presenting cells that have phagocytosed allograft cell proteins
acute
can cause a prolonged and potentially life-threatening asystole in a transplanted (=denervated) heart
adenosine
blocking this is a reason to take drugs such a s prednisone, cyclosporine and mycophenolate
allograft rejection
xanthine oxidase inhibitor used to prevent gouty arthritis and uric acid nephropathy in patients predisposed to hyperuricemia or having it due to excess cell turnover from cancer +/- chemotherapy; its use mandates a reduction in azathioprine dosage
allopurinol
developed in horses or rabbits, administered to selectively inactivate/destroy T cells as part of transplant induction therapy or when they are causing acute rejection of a transplanted organ despite other immunosuppressive therapy
antithymocyte globulin
anti-proliferative agent that helped make allogeneic transplantation possible, it is somehow more effective at blocking de novo purine synthesis and DNA replication than direct administration of its active metabolite, 6-mercaptopurine
azathioprine
mouse monoclonal antibody against human IL-2 receptor that can be used to inhibit T cell activation/proliferation as part of transplant induction therapy, tolerability was improved by creating a chimera in which the antibody contains a human constant region
basiliximab
proliferate and differentiate into antibody-producing plasma cells when fragments of a molecule that was captured by the surface expression of their unique antibody and then inserted into MHC class II antigens on their surface is recognized as foreign by a helper T cell
B cells
major adverse effect of most anti-proliferative drugs, increases susceptibility of transplant recipient to infection and bleeding
bone marrow suppression
most effective immunosuppressive drugs in routine use
calcineurin inhibitors
T cell population that surveys MHC class II molecules for unrecognized peptide fragments derived from phagocytosis, and, upon recognizing a foreign molecule, activates macrophages, stimulates production of antibodies, etc.
CD4
T cell population that surveys cell protein synthesis by examining fragments of those proteins inserted into the MHC class 1 proteins on their cell surface, and destroys those cells that are recognized as synthesizing foreign proteins
CD8
refers to organ rejection occurring over months to years for which there is ~no effective therapy, characterized by interstitial fibrosis, thickened vascular walls, etc.
chronic
pharmacological dosages of exogenous glucocorticoids can also cause this
Cushing Syndrome
first drug discovered that caused immunosuppression without bone marrow suppression, its binding to cyclophilin blocks calcineurin-mediated dephosphorylation of NFAT
cyclosporine
refers to the unpleasant consequences (e.g., fever, chills, dyspnea, nausea, possibility of anaphylactoid shock) associated with the administration of an antibody generated in a different species; can be especially bad during initial administration but then decreases over time, in part because of concurrent administration of glucocorticoids
cytokine release syndrome
risk of developing this is significant following renal transplantation, especially when immunosuppressive drugs are added to glucocorticoids
diabetes
a sirolimus-like drug but with a shorter half-life (~30 hrs vs 62 hrs), means steady-state levels can be achieved faster and also that drug will disappear faster if discontinued due to adverse effects
everolimus
pharmacological doses blunt acute organ rejection in part by suppressing NFkappaB driven gene expression in cells triggered by the recognition of a foreign antigen
glucocorticoids
its de novo synthesis is blocked by mycophenolate; stops proliferation of lymphocytes since they cannot use purine salvage pathways like other cells
guanine
potential cosmetic challenge with cyclosporine that is not a problem with tacrolimus
hirsutism
organ rejection that occurs within minutes due to preformed antibodies and complement activation
hyperacute
side effect of therapy with cyclosporine and sirolimus but not tacrolimus
hypercholesterolemia
consequence of the renal afferent arteriolar constriction caused by cyclosporine and tacrolimus in solid organ transplant recipients
hypertension
proinflammatory signaling molecule released by antigen-presenting cells that facilitates activation of lymphocytes
IL-1
molecule released by activated T cells that binds to receptors on their surface to promote the characteristic T cell response (= growth, proliferation and differentiation of effector T cells)
IL-2
the first and still by far most transplanted organ
kidney
organ in addition to liver for which sirolimus is contraindicated as anti-rejection therapy after transplantation
lung
accumulation of lymph in unusual space (e.g., retroperitoneal cavity after renal transplant), risk is increased by sirolimus
lymphocele
cell population unable to use guanine salvage pathways, therefore must synthesize new guanine during proliferation (= reason for cell-selectivity of mycophenolate)
lymphocytes
approved for use only when there is a glucocorticoid-resistant flare-up in the acute rejection of a transplanted organ
muromonab CD3
non-competitive reversible inhibitor of inosine monophosphate dehydrogenase used for its antiproliferative effects in lymphocytes (they need this enzyme to synthesize guanosine nucleotides)
mycophenolate
dose-limiting for both cyclosporine and tacrolimus, especially cyclosporine
nephrotoxicity
its migration into the lymphocyte nucleus after its dephosphorylation by calcineurin is crucial for the generation of gene products such as IL-2 that are characteristic of T cell activation
NFAT
among the cells that contributes to acute allograft rejection, for example, via antibody-dependent cell-mediated cytotoxicity
NK cells
widely known name for muromonab-CD3 (“nab” rather than “mab” is correct spelling), the original and still-used mouse monoclonal antibody against human CD3 (= T cell receptor) that causes its rapid internalization and thereby prevents T cell activation
OKT3
example of a drug that causes sequestration of circulating lymphocytes and also decreases their number via apoptosis
prednisone
wise to take extra measures to prevent this if taking anti-proliferative agents
pregnancy
reason, for example, for administering basiliximab or rATG immediately before kidney transplantation and for a few days after, during what is referred to as “transplant induction therapy”
prophylaxis
does not occur when nifedipine or hydralazine are administered to a heart transplant recipient
reflex tachycardia
attempts to minimize this are the reason that sirolimus is added to lowered doses of cyclosporine or tacrolimus
renal damage
binds to FKB12, but inhibits protein kinase mTOR, which in lymphocytes is an important downstream signaling component of IL-2 receptor-stimulated proliferation and differentiation
sirolimus
aka FK-506, binds to the immunophilin FKB12 to inhibit calcineurin phosphatase activity; exerts beneficial effects in organ transplantation similar to those caused by cyclosporine
tacrolimus
effect observed with sirolimus, means that foreign antigens present during its use are not rejected immediately when/if sirolimus is discontinued
tolerizing
encompasses the dream of transplanting pig organs into humans
xenotransplantation
the only NRTI that is a guanosine analog, relatively safe in most but can cause a unique and potentially fatal hypersensitivity syndrome in those with the HLA-B*5701 locus
abacavir
symptoms of this appear when HIV RNA copy numbers are high in plasma and CD4+ lymphocyte numbers are low
AIDS
government run website that provides latest consensus guidelines for treatment of HIV in the US
aidsinfo
when boosted, a first-choice protease inhibitor for treatment-na‹ve HIV patients due to its long half-life and reduced side effects, but can cause unconjugated hyperbilirubinemia not associated with hepatitis
atazanavir
carries by far the greatest risk of transmitting HIV, but now a negligible cause for HIV transmission in the US (risk ~ 1:1.4 million)
blood transfusion
having this fall to <350 cells/mm3 currently has an AI level of support for initiation of antiretroviral therapy
CD4 count
common side effect of efavirenz, but typically subsides and rarely leads to discontinuation of the drug
CNS toxicity
emergence of this tropism in HIV renders it resistant to maraviroc
CXCR4
cytochrome P450 isozyme that is inhibited, induced, etc., by a wide range of drugs including several antiretroviral drugs, which leads to potentially troublesome drug interactions
CYP3A4
when boosted, a first-choice protease inhibitor for treatment-na‹ve HIV patients due to its long half-life and reduced side effects, but can cause sulfa drug hypersensitivity reactions
darunavir
prodrug formulation of tenofovir, a phosphorylated adenosine analog, to overcome its otherwise poor bioavailability
disoproxil
HIV integrase strand inhibitor with ~ 14 hr half-life (i.e., suitable for once per day dosing)
dolutegravir
the current NNRTI of choice for treatment-na‹ve HIV patients, in part because it is co-formulated with tenofovir and emtricitabine for convenient once/day dosing; teratogen
efavirenz
HIV integrase strand inhibitor with suitable for once per day dosing due to prolongation of half-life with cobicistat
elvitegravir
cytidine analog, one of the least toxic anti-retroviral drugs and an NRTI of first choice for HIV treatment-na‹ve patients due to its long half-life and co-formulation with tenofovir +/- efavirenz
emtricitabine
a 36 aa peptide that inhibits formation of a 6-helix bundle critical for HIV fusion with the host cell membrane, drug is a last resort since expensive and must be administered subQ 2X/day
enfuvirtide
HIV gene that encodes for gp120 and gp41
env
NNRTI approved for use in treatment-experienced people infected with HIV since it still works after HIV mutations that cause resistance to some other NNRTI
etravirine
HIV gene that contains the nucleocapsid core and matrix proteins
gag
also sensitive to some HIV drugs such as tenofovir disoproxil fumarate and emtricitabine; discontinuation of these drugs can cause a disease flare-up
HBV
cells infected with HIV typically only have one copy of this, unlike the virion which characteristically possess two copies of its precursor
HIV DNA
early protease inhibitor requiring 3X/day dosing, now perhaps more noteworthy for its ability to cause crystaluria
indinavir
enzyme responsible for insertion of retroviral DNA into the human genome, and an excellent drug target since mammalian genomes lack enzymes with this capability
integrase
risk of acquiring HIV infection during this is fortunately much lower than during childbirth or blood transfusion
intercourse
earlier cytidine-like NRTI, interesting in that HIV can develop resistance to it relatively quickly but doing so increases reverse transcriptase fidelity, slows replication, and thereby helps to increase the long-term effectiveness of zidovudine
lamivudine
~irreversible disfiguring re-distribution of body fat associated with HIV and its treatment
lipodystrophy
HIV protease inhibitor only available as a boosted combination, inhibits both HIV-1 and HIV-2, and often works after failure of another PI-containing regimen
lopinavir
will block HIV entry if an expensive test with a long turnaround time shows that the virion requires the CCR5 co-receptor
maraviroc
blockade of DNA polymerase here is thought to be responsible for some of the adverse effects associated with some NRTI
mitochondria
typically 4-5 are required for HIV to develop resistance to protease inhibitors, reason resistance is slow to develop and seldom a cause for treatment failure
mutations
among the toxicities associated with some NRTI that is thought to be due to inhibition of DNA polymerase gamma
myopathy
ending of generic drug name that identifies the drug as an HIV protease inhibitor
navir
an NNRTI, early studies with it demonstrated the importance of combination therapy in treating HIV after the virusin ~1/3 of patients developed resistance to it after a single monotherapy exposure
nevirapine
class of drugs that selectively inhibits only HIV-1 reverse transcriptase; binds to a distant hydrophobic pocket in a manner that causes a conformational change and noncompetitively inhibits enzymatic activity
NNRTI
a two-drug combination from this antiretroviral drug therapy class with zidovudine as its prototype provides the backbone for current HIV treatment strategies
NRTI
aka MDR1, a transporter that interacts with many drugs and site at which competition can influence the drug toxicities
p-glycoprotein
required of NRTI for them to be active
phosphorylation
HIV gene that contains reverse transcriptase, protease, integrase, etc.
pol
the combination of tenofovir disoproxil fumarate and emtricitabine is this for treatment-naive HIV patients due to its safety and efficacy, and also due to the convenience of a once/day co-formulation +/- efavirenz
preferred NRTI backbone
should be given anti-retroviral therapy as soon as possible, irrespective of viral load or CD4 count, but efavirenz should not be used during the first trimester
pregnant woman
HIV enzyme that cleaves at the N-terminal side of Pro residues in the long polypeptides (e.g., gag, pol) packaged into newly budded virions to release the enzymes and cell components required for their metamorphosis into a mature virus capable of causing infection
protease
first generation integrase inhibitor, seems likely to be displaced from preferred therapy list by new drugs elvitegravir and dolutegravir since their longer half-lives permit once daily dosing
raltegravir
reason to avoid some antiretroviral drugs such as indinavir and enofovir and/or decrease the dosages/use with caution
renal insufficiency
weaker HIV protease inhibitor discovered to be a potent inhibitor of CYP3A4, reason it is now routinely used to “boost” other protease inhibitors
ritonavir
first HIV protease inhibitor, its short half-life caused a troublesome pill burden and it is among the agents well-known for promoting irreversible lipodystrophy with long-term use
saquinavir
among early thymidine NRTI, notable for causing many of the toxicities associated with the drug class including CNS toxicity, fat wasting, and the ability to cause lactic acidosis and hepatic steatosis
stavudine
portion of generic drug name indicating that the drug is an HIV integrase inhibitor
tegravir
adenosine analog that is the only NRTI nucleotide (i.e., has a phosphate already attached, so only needs 2 more to be active), an NNRTI of choice due to its relative safety, long half-life and co-formulation in once/day pills
tenofovir
NRTI do this during reverse transcriptase mediated synthesis of proviral DNA
terminate elongation
reason for a thorough evaluation of patient history and contemplation of new strategy rather than adding a single new drug to an HIV treatment regimen or stopping treatment altogether
treatment failure
thymidine analog and the first anti-retroviral drug discovered, this NRTI is still in widespread use in resource-poor settings due to its well-known tolerability, toxicity and efficacy profiles
zidovudine
