Immuno Exam 2: Drug therapy in Transplantation

transplant

Surgical operation to give a functioning human organ or tissue to someone whose organ or tissue has stopped working or is close to failing

solid organs that can be transplanted

- heart

-lungs*

-liver*

-kidney*

-pancreas

-small intestine

* live donor possible

tissues that can be transplanted

-corneas

-heart valves

-bone

-bone marrow

-blood vessels

-skin

common causes of kidney transplant

-diabetes

-HTN

-glomerulonephritis

-polycystic kidney disease

-drug-induced kidney failure

-infection

-kidney stones

main drug that causes drug-induced kidney failure

NSAIDs

common causes of liver transplant

-Hep C

-nonalcoholic seatohepatitis (NASH)

-alcoholic liver disease

-autoimmune hepatitis

-primary biliary cirrhosis

-primary sclerosing cholangitis

-acute liver failure (can be drug-induced)

-malignancy

which drug is a common cause of acute liver failure

acetaminophen

common causes of heart transplant

- heart failure

-hereditary conditions

-infection (previous) leading to cardiomyopathy (can be bacterial or viral)

common causes of lung transplant

-cystic fibrosis

-chronic obstructive lung disease (emphysema)

-pulmonary fibrosis

-pulmonary hypertension

most common organ transplant at YNHH (Yale)

kidney

what is the organization that decides how to allocate organs?

united network for organ sharing (UNOS)

functions of UNOS (united network for organ sharing)

-manages waitlist

-matches donors to recipients

-maintains database for all transplants in US

-educates the public

2 types of organ donation

living and decease donor

types of living donors

living related (paired exchange donors)

living unrelated (altruistic donation)

types of deceased donors

-brain death (better success)

-cardiac death

causes of graft failure

• Acute rejection (Cellular or Antibody-mediated)

• Graft thrombosis

• Recurrent disease

• Non-compliance to medications

• Death

risk factors for graft rejection

sensitization

-prior transplant

-pregnancy

-blood transfusions

ventricular assist device (VAD)

african american

what is human leukocyte antigen synonymous to?

human major histocompatability complex (MHC)

function of HLA (human leukocyte antigen)

identify self vs non-self (this function is polymorphic/depends on genetics)

2 classes of MHC

Class I and II with II only being on APCs

where is MHC gene located?

chromosome 6

signal 1 steps

antigen binds to MHC on APC and allows it to interact with TCR

this activates calineurin which phosphorylates NFAT

pNFAT goes into the nuceleus to promote transcription (TC proliferation)

signal 2 steps

CD80/86 on APC connects to CD28 on TC

causes synapse formation

signal 1 cannot happen without signal 2

signal 3 steps

IL-2 cytokine binds to CD25 on TC

activates CD25, JAK3, and PI-3K

these then activate mTOR which then goes into the nucleus to promote T cell proliferation

when is the intensity of immunosuppression greatest?

greatest during the 1st year

goals of induction therapy

-reduce incidence of acute rejection in 1st year

-treat and prevent delayed graft rejection function (kidney)

-delay initiation of calcineurin inhibitor (CNI) because it's nephrotoxic

polyclonal induction vs monoclonal induction

poly binds to many TC sites while mono only binds to 1

types of polyclonal induction (with brand names)

anti-thymocyte globulin (Thymoglobulin, Atgam)

types of monoclonal induction (with brand names)

basiliximab (Simulect)

alemtuzimab (Campath)

T-cell depleting induction therapies (with brand names)

antithymocyte globulin (Thymoglobulin, Atgam)

alemtuzumab (Campath)

T-cell non-depelting induction therapies (with brand names)

basiliximab (Simulect)

MOA of basiliximab

IL-2 receptor antagonist

-binds to alpha chain of CD25 of IL-2 receptor complex and inhibits IL-2 bonding

non TC depleting agent

basiliximab brand name

simulect

features of anti-thymocyte globulin

-polyclonal antibody

-T-cell depleting agent

-T-cell depletion via complement-dependent cell lysis

uses of anti-thymocyte globulin

used as induction and anti-rejection agent

animal used for Atgam

horse

animal used for thymoglobulin

rabbit

thymoglobulin

-rabbit derived polyclonal antibody

-induction or rejection treatment

-weight-based dosing for 3-5 days (dose adjusted for WBC + Platelets)

atgam

-equire-derived

-high rates of batch inconsistency so not preffered (rarely used)

- wieght based dosing but less potent than thymoglobulin

patient survival and graft survival of atgam vs thymoglobulin

patient survival is simular in the first 30 months but then atgam rates go down

graft survival immediately is more successful in thymoglobulin

adverse effects of anti-thymocyte globulin

-cytokine release syndrome

-serum sickness

-leukopenia, thrombocytopenia

cytokine release syndroem symptoms

hypotension, rigors, fevers, nausea, vomiting, cardiac arrhythmias, MI, cardiac arrest, death

premedication with anti-thymocyte globulin

required 30 mins before infusion

-acetaminophen

-diphenhydramine

steroids

duration of anti-thymocyte globuin vs non-depleting TC therapy

anti-thymocyte is TC depleting and it's much longer lasting

alemtuzumab brand name

Campath

MOA of alemtuzumab

binds to CD25 on the surface of B and T cells to flag for apoptosis

is a TC depleting agent

effect of alemtuzumab

removes all circulating T cells

-antibody dependent cellular toxicity

-complement dependent cytotoxicity

-apoptosis

-full recovery of TC takes >12 months

adverse effects of alemtuzumab

-IV administration--> cytokine release syndrome

-SC- better tolerated

-leukopenia

-thrombocytopenia

examples of when T Cell non-depleting agents should be used

-low risk of rejection (especially with living donor or >65)

-HIV, hepC (T cells regulate disease state)

-liver transplant

examples of when T Cell depleting agents have a high risk of rejection

-deceased donor

-co-morbidities

-african american

-previous transplant

-younger age

risks of induction therapy

-increased risk of infection

-increased incidence of malignancy (Post transplany lymphoproliferative disease)

-toxicity of drug therapy (cytokine release syndrome and serum sickness)

-expensive

goals of maintenance therapy

-reduce incidence of acuute rejection

-prolong graft survival (avoid nephrotoxicity)

-prolong pt survival

-balance infection risk

-minimize side effects

-facilitate adherence

classes of maintenance immunosuppression

-calcineurin inhibitors (CNI)

-co-stimulatory blocker

-antiproliferatives/antimetabolites

-mammalian target of rapamycin inhibitors (mTOR)

-corticosteroids

which drugs are calcineurin inhibitors and brand names

cyclosporine (neoral/sandimmune/CSA)

which drugs are co-stimulatory blockers and brand names

belatacept (nulojix)

which drugs are antiproliferatives/antimetabolites and brand names

mycophenolate (cellcept/myfortic/MMF)

azathioprine (Imuran/AZA)

which drugs are mTOR inhibitors and brand names

sirolimus (Rapamune/RAPA)

everolimus (Zortress)

Calcineurin inhibitor (CNI) MOA

form a complex that binds with calcineurin preventing expression of T cell activators (like IL-2)

what is the backbone of current immunosuppression

calcineurin inhibitors (CNIs)

types of calcineurin inhibitors

tacrolimus and cyclosporine

what are CNIs (tacrolimus and cyclosporine) substrates of?

CYP3A4 and p-gp

brand names and dosage forms of tacrolimus

IR (prograf)- can be SL

XR/XL (astagraf XL and envarsus XR)

not all interchangeable 1:1

which tacrolimus agent is preferred and why?

Envarsus XR is preferred because it doesn't rapidly peak in dose which causes more side effects

more constant AUC/concentration

modified cyclopsorine brand names

neoral and gengraf

non-modified cyclosporine brand name

sandimmune

modified vs non-modified cyclosporines

both available as PO and IV formulations

NOT interchangeable

distinct adverse effects of tacrolimus

-pancreatic islet toxicity (diabetes)

-alopecia

distinct adverse effects of cyclosporine

-hirtuism (excess hair growth)

-ginigval hyperplasia (enlarged gums)

-hyperlipiedmia

common adverse effects between cyclosporine and tacrolimus

-nephrotoxicity

-neurotoxicity

-hypertension

-hyperkalemia

-hypomagnesmia

trough concentration for tacrolimus

5-15ng/mL

trough concentration for cyclosporine

50-300ng/mL

tacrolimus and cyclopsorine drug monitoring

-dose/trough levels

-organ and institution specific

-for life

when does trough level of cyclosporine and tacrolimus have to be modified?

-induction agent

-additional immunosuppressive agents

-kidney dysfunction

-rejection history

-infection history

when to measure trough levels of CNIs

30 mins prior to the next dose

don't take CNI prior to blood draw because it can lead to innacurate levels

mycophenolate mofetil brand name

CellCept

mycophenolate sodium brand name

Myfortic

MOA of mycophenolates

inhibits inosine monophosphate dehydrogenase (IMPDH) and prevents de novo protein synthesis in lymphocytes

active agent is mycophenolic acid (MPA)

Cellcept to Myfortic acid conversion

1000mg of CellCept = 750mg Myfortic

adverse effects of mycophenolate

-GI issues

-leukopenia, thrombocytopenia, anemia

-teratogenic

why is there REMS for mycophenolate

first trimester pregnancy loss

congenital malformations

REMS for mycophenolate

-must provide education and contraception counseling

-only for women because it doesn't affect sperm

pregnancy planning with mycophenolate

-stop med for 6 weeks

-switch to alternative agent

azathioprine brand names

Imuran, azasan, AZA

MOA of azathioprine

incorporates into cellular DNA interfering with RNA synthesis and metabolism

-inhibits gene replication--> no TC activation

-inhibits proliferation of promyelocytes in marrow

Mammalian target of rapamycin (mTOR) inhibitors MOA

-binds to m-TOR which results in arrest of the cell cyle at G1

-inhibits proliferation of many cell lines (lymphoid, CNS, hepatic, melanocytes)

trough level monitoring for which agents

CNIs

mTOR inhibitors

mTORs are a substrate of what

CYP3A4

when to consider mTOR inhiitors

-history of cancer

-intolerance to CNIs

-history of viral infections (BK virus)

adverse effects of mTOR inhibitors

• Hepatic artery thrombosis

• Impaired wound healing

• Nephrotoxicity, neurotoxicity (Only when used with CNI)

• Interstitial pneumonitis/alveolar hemorrhage

• Thrombocytopenia, leukopenia

• Hyperlipidemia

• Peripheral edema

• Mouth ulcers

belatacept brand name

Nulojix

MOA of belacept

binds to surface receptor (CD80/86 AKA B7 and B7-2) of APCs, stop signal 2

inhibits interaction between APCs and T-cells needed for T-cell activation

replacement of CNIs with co-stimulation inhibitor

-avoids nephrotoxicity

-one monthly infusion

what is co-stimulation inhibitor approved for

kidney transplant recipients ONLY

BBW of co-stimulation inhibitors

-post transplant lymphroliferative disorder

-only used in Epstein-barr positive pts

-use in liver patients is not recommended due to increased risk of graft loss and death

adverse effects of co-stimulation inhibitors

-anemia

-headache

-N/V/D

corticosteroids are given to which organ transplant paient

ALL

tapered rapidly over 1st 5 days

Glucocortioid MOA

acute effects (mins)

-decreased vasodilation and capillary permeability

-decreased leukocyte migration

binding to Grs

-inhibition of NFKB and decrease in pro-inflammatory ctokines

reduces TCs, BCs, and APCs

side effects of corticosteroids

• Hepatic artery thrombosis

• Impaired wound healing

• Nephrotoxicity, neurotoxicity

• Only when used with CNI

• Interstitial pneumonitis/alveolar hemorrhage

• Thrombocytopenia, leukopenia

• Hyperlipidemia

• Peripheral edema

• Mouth ulcers

not common in organ transplant due to low doses/tapering

which signal do CNIs affect

signal 1

which signal does belatacept affect

signal 2