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Pharmacy Y3- Cardiovascular diseases > Week 10- Solid organ transplant > Flashcards

Week 10- Solid organ transplant Flashcards

1
Q

14:27 what are the different types of transplants?

A
  • Heart
  • Lung
  • Liver*
  • Simultaneous Pancreas and Kidney transplant (SPK)*
  • Pancreas*
  • Kidney*
  • Bowel*
  • Multi-visceral*
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2
Q

where are the organs from?

A 
• Deceased donor
• Living donor (altruistic= anyone or
directed=to someone you know)
- Liver section
- Kidney
•Exclusion
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3
Q

what patients can’t be a donor?

A
  • ebola
  • active cancer
  • HIV patients
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4
Q

what is the process for a transplant?

A
  • transplant assessment= must have something wrong that cant be cured any other way, reviewed by a MDT (multidisciplinary team to see if they are appropriate for the waiting list)
  • waiting list= exclusion criteria e.g. patient had other diseases life expectancy less than 2 years, donor-recipients blood groups,
  • wait for a phone call
  • the recipents immune system is the biggest barrier, immunosuppression
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5
Q

what are the aims for solid organ transplant?

A
  • Increased life expectancy

* Increased QoL

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6
Q

what is the biggest problem for solid organ transplant?

A

-recipents immune system

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7
Q

what is the solution for the biggest problem for solid organ transplant?

A

using immunosuppression

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8
Q

what are the aims for immunosuppression?

A

-prevent graft rejection
-induction of tolerance for the organ
-reduce risk like
• Side effects
• Infections
• Malignancy
• Post Transplant
Lymphoproliferative Disease

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9
Q

what is a graft?

A

a surgical procedure to move tissues from one site to another on the body, or another creature without bringing its own blood supply

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10
Q

what are the different types of grafts?

A
  • xenografts
  • autografts
  • isografts
  • allografts
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11
Q

what is a xenografts?

A

between different species = greatest immune response = Rejection

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12
Q

what is an autograft?

A

from one part of the body to another on the same individual = No rejection

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13
Q

what is an isograft?

A

grafts between genetically identical individuals = no rejection

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14
Q

what is an allograft?

A

between members of the same species = varied response dependent on degree of histocompatibility of donor and recipient (but
also type of organ)

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15
Q

what are the antigens responsible for rejection of the organ called?

A

histocompatibility antigens and are prodcuts of the hstocompatibility genes

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16
Q

what is the loci of the genes that cause the most vigour rejection ?

A

major histocompatibility complex MHC AND IN HUMANS ITS CALLED HUMAN LEUKOCYTE ANTIGEN HLA

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17
Q

what are the 2 classes of MHC split into?

A

MHC I and MHC II

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18
Q

What are MHC I?

A

normally expressed on all nucleated cells and present antigenic peptides from inside the cell to CD8 T cells

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19
Q

what are MHC II ?

A

are only expressed on professional antigen presenting cells, activated
macrophages and B cells and present extracellular antigens to CD4 T cells

20
Q

why are MHC molecules important?

A

part of a physiological function where presents antigens to T cells as they are only recognised when in complex with MHC molecules

21
Q

what immune systems are involved in transplants?

A

adaptive (both cellular and

humoral response) and innate mechanisms

22
Q

what cells are important and involved in rejections of grafts?

A

T cells

23
Q

what do T cells do?

A

T cells become activated,

undergo clonal expansion and differentiate to express effector functions.

24
Q

what are the 2 ways to minimise/control the host immune resposne to a transplant?

A
  • HLA compatibility

- immunosuppression

25
Q

how are genes in the MHC I and MHC II complex affecting rejection?

A

-genes at certain loci of the MHC I and MHC II COMPLEX PLAY a stronger or lesser of a role causing rejection. Strongest determinants is the HLA-DR for matching between donor and recipient , decrease chance of rejection

26
Q

what are the benefits of good HLA-compatibiltiy?

A

• Better graft function
• Fewer episodes of rejection
• Longer graft survival
• Possibility of reduced immunosuppression (potential for reduced infection and
malignancy risk)
• Decreased risk of sensitisation increasing issues with further transplants if
required

27
Q

what are the two phases of immunosuppression?

A

induction and maintaence

28
Q

what is the induction phase?

A

the start immunosupression needed for as long as the graft is occuring for transplant. high dose due to transplant being a foreign molecule being introduced

29
Q

what is the maintencence immunosuppression?

A

a lower dose of IS after the transplant

30
Q

what are medication used for indcution immunosuppressant?

A
  • corticorsteriod
  • basiliximab
  • alemtuzumab
  • antithymocyte glbulin (ATG)
31
Q

11:06 what are the medication used for maintanence?

A
  • Ciclosporin / Tacrolimus
  • Azathioprine / Mycophenolate
  • Corticosteroids
  • Balatacept
32
Q

what is basilizimab?

A

-for induction
it is a monoclonal antibody acts against IL-2 receptror(CD25 T cells must be activated for this to be expressed)
• Inhibits differentiation and proliferation but is minimally T cell depleting
• Minimal adverse effects (no pre-med/specialist monitoring required)
• Given at induction and 3-4 days post surgery

33
Q

what is alemtuzumab?

A

-for induction
• Humanised, rat IgG monoclonal antibody directed against CD52 cell surface
antigen causing cell lysis and prolonged depletion (also inhibits most monocytes, macrophages and natural killer cells)
• Associated with first dose reaction, neutropenia, anaemia, pancytopenia
(rare) and autoimmunity (haemolytic anaemia, thrombocytopenia and
hyperthyroidism)
• Used to treat episodes of rejection

34
Q

what is Antithymocyte globulin?

A

-for induction
-IgG from horse or rabbits
-Blocks a large number of T cell membrane proteins (including CD2, CD3, CD45), causing
altered function, lysis and prolonged T cell depletion
• Cell lysis can be responsible for cytokine release syndrome – fever, chills, hypotension
• Associated with thrombocytopenia, leukopenia, occasional serum sickness and allergic reactions
• Pre-medication – paracetamol, chlorphenamine and corticosteroid
• Close monitoring required
• Used to treat episodes of rejection

35
Q

what is corticosteriods?

A

-for induction
• Also used in maintenance therapy
• S/E: adrenal suppression, HTN, diabetes, osteoporosis, Cushing’s syndrome, GI, Wt gain,
hyperlipidaemia, infection, etc….

36
Q

how long do patients take these maintenance drugs for?

A

theyll take one for a least the rest of thier life

37
Q

what ciclosporin?

A

-for maintenance
-its a Calcineurin inhibitor
-• Is a metabolite of fungal, Tolypocladium inflatum
• Binds to cyclophilin (an immunophilin) to form a complex. Complex inhibits
calcineurin phosphatase suppressing T cell activation by inhibiting cytokine
production, primarily IL-2
• Concentration related adverse effects: nephrotoxicity, hypertension,
hyperlipidaemia, gingival hyperplasia, hirsutism, tremor
• May also induce: haemolytic uraemic syndrome, diabetes mellitis
• Twice daily dosing regime (adjusted to levels)
• Therapeutic drug monitoring
• Brand prescribing required – Neoral / generics
• Metabolised by the CYP 450 enzymes = NUMEROUS interactions
• Major positive impact on rejection and survival following transplant

38
Q

what is tacrolimus?

A

-for maintence
-its a Calcineurin inhibitor
• Macrolide antibiotic derived from Streptomyces tsukubaensis
• Binds to FK506-binding protein 12 (an immunophilin) to inhibit calcineurin and T cell
activation (binds a different intracellular protein to ciclosporin but has subsequent
same mechanism of action)
• More potent than ciclosporin
• Similar S/E to ciclosporin (nephrotoxicity and haemolytic uremic syndrome) but
lower incidence of hypertension, hyperlipidaemia, hirsutism and gum hyperplasia
and higher incidence of diabetes mellitus and neurotoxicity
• Once or twice daily dependent on brand and transplant
• Brand prescribing required – Prograf, Advagraf, Adoport
• Best absorption on an empty stomach (food decreases bioavailability)
• Therapeutic drug monitoring – trough level
• Metabolised by the CYP 450 enzymes = NUMEROUS interactions

39
Q

what are some improtanct considerations for the calcineurin inhibitor?

A

• Brand prescribing
• Difference in bioavailability with different formulations
• Oral cyclosporin dose approximately 3 times the IV dose
• Oral dose of tacrolimus approximately 3-5 times the IV dose
• Ciclosporin has specific information regarding the dilution of the solution
• S/E more likely to occur above the therapeutic range but can be
idiosyncratic and occur at normal concentrations
• Therapeutic drug monitoring

40
Q

what is azathioprine?

A

-for maintenance
-its a antiproliferative drugs
-Summary – 6-MP is converted to thioguanine nucleotides which interfere
with DNA synthesis. Another metabolite can also inhibit purine synthesis.
• Inhibiting proliferation of T and B cells
• Main S/E – Haematological (dose dependent myelosuppression can occur
with over 50% of patients developing leukopenia – reversed by
reducing/stopping the drug), thrombocytopenia (reversed by
reducing/stopping the drug); N&V (alleviated when given with food or in
divided doses)
• Close FBC monitoring required
• Once daily dosing
• Interaction – ALLOPURINOL (reduce the azathioprine dose to ¼)

41
Q

what is Mycophenolic acid (MPA)?

A

-for maintenance
-its a antiproliferative drugs
• MPA blocks inosine monophosphate dehydrogenase, the enzyme required
for de novo synthesis of guanosine monophosphate nucleotides. This
blocks purine synthesis preventing B and T cell proliferation
• More potent than azathioprine with greater reduction in acute rejection
• Main S/E: Haematological – neutropenia, leukopenia, mild anaemia;
gastrointestinal – diarrhoea can be dose limiting (EC MPA (Myfortic)may
improve this)
• Monitor FBC
• Twice daily dosing
• Important drug interactions

42
Q

what is sirolimus?

A

-for maintenance
-is a mTOR inhibitor
• Used as an alternative to calcineurin inhibitors and antiproliferatives or
in combination with calcineurin inhibitors
• Formally known as rapamycin, sirolimus is a drug that inhibits the
mammalian target of rapamycin (mTOR)
• Sirolimus firstly binds the immunophilin FKBP12 forming a complex that
inhibits mTOR
• mTOR is a serine/threonine protein kinase involved in regulation of cell
growth, proliferation and of protein synthesis and ribosome biogenesis
• Blockade of mTOR inhibits the cellular proliferation response to a variety
of cytokines including IL-2
• Therapeutic drug monitoring required
• S/E:
• Less nephrotoxic than CNI
• Less likely to cause diabetes
• Risk of life threatening pneumonitis (resolves after treatment withdrawal)
• Impair wound healing (mTOR inhibition of fibroblast response to fibroblast growth factor) – not
used immediately post transplant
• Hyperlipidaemia,thrombocytopenia
• Metabolised by the CYP 450 enzymes = NUMEROUS interactions
• Administer consistently (with or without food)

43
Q

what is balatacept?

A

-for maintenace
-its a Selective T cell co-stimulation
blocker
• Binds CD80 and CD86 receptors on the antigen presenting cell
preventing CD28 on the T cell from binding
• Dosing divided into two phases:
• Initial phase, IV day1 and 5 and at the end of weeks 2, 4, 8 and 12
• Maintenance phase, IV end of week 16 and every 4 weeks thereafter
• Risk of post transplant lymphoproliferative disease
• Used as an alternative to CNI
• Comparison studies have shown equivalent patient and graft survival but a higher incidence of
acute rejection

44
Q

what is combination therapy and the beneift for maintence ?

A

• As more therapy has become available the use of combination therapy with action at different sites has been shown to have better outcomes
• Reduced steroid dose
• Better patient outcomes – reduced rejection
• Dependent on type of transplant and perceived immunosuppressive
challenge
• Initiated at the time of surgery
• Generally will have at least one continued life-long

45
Q

what are some complications for immunospression?

A
  • individual side effects
  • high chance of infection
  • malignancy is higher espeically those caused by viral aetiology

Pharmacy Y3- Cardiovascular diseases (8 decks)

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