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Pharmacology > Immunosuppressant and Immunomodulatory Drugs > Flashcards

Immunosuppressant and Immunomodulatory Drugs Flashcards

1
Q

Describe the timing and cause of hyperacute rejection.

How could you avoid hyperacute rejection?

A

Occurs within minutes of transplant
Caused by preformed reactive antibodies

Avoid it by crossmatching the blood types and tissues before transplant

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2
Q

Describe the timing and cause of acute rejection

A

6-12 months post transplant

T cell mediated rejection

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3
Q

Describe the timing and cause of chronic rejection

A

Months-years after transplant

Due to fibrosis damaging the graft blood vessels

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4
Q

In general, what is the medical approach to immunosuppression in transplant patients?

A

Triple therapy regimen.
Target 3 different aspects of the immune system to prevent rejection. This also allows you to lower the dose of each regimen, thus decreasing risk of adverse effects

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5
Q

What are the two glucocorticoids used in immunosuppressive therapy?
Which is a pro-drug and which is an active drug?

A

Prednisone (prodrug)

Prednisolone (active drug)

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6
Q

Glucocorticoids

MOA

A

They are steroid hormones that bind intracellular receptors, causing inactivation of proinflammatory and regulatory genes

Decrease number of circulating leukocytes

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7
Q

When are high doses of IV steroids (Prednisone/Prednisolone) used?

A

Acute rejection episodes

Graft vs Host Disease in bone marrow transplant

Treatment of Cytokine Release Syndrome

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8
Q

Glucocorticoids

Adverse Effects associated with chronic treatment

A 
Increased risk of infection
Hyperglycemia
HTN
Hyperlipidemia
Obesity
High risk of exacerbating preexisting diabetes or developing diabetes
Osteopenia
Cataracts
Growth retardation in kids
Poor wound healing
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9
Q

Glucocorticoids

How are they typically administered to prevent adverse effects? Describe how cessation of glucocorticoid therapy occurs.

A

Slow taper over the first month

You should NOT rapidly withdraw from Glucocorticoid therapy due to risk of having an acute adrenal crisis

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10
Q

Azathioprine

MOA

A

Prodrug of 6-mercaptopurine.

Then gets converted to 6-TIMP, which inhibits de-novo synthesis of purines.

TIMP also gets metabolized to inhibit Rac1, leading to inhibition of T cell activation.

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11
Q

Azathioprine

Indications

A 
Prophylaxis prevention of graft rejection
Autoimmune diseases (RA, Crohn's, MS)
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12
Q

Azathioprine

Adverse Effects

A 
GI effects (nausea, diarrhea, vomiting)
Leukopenia
Thrombocytopenia
Increased infection risk
Increased malignancy risk
Hepatotoxicity
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13
Q

Azathioprine

Drug Reactions

A

Reacts with Allopurinol and Febuxostat (Xanthine oxidase inhibitors used in the treatment of gout)
- Causes elevated 6-mercaptopurine levels

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14
Q 
Mycophenolate Mofetil (MMF)
MOA
A

Prodrug of mycophenolic acid (MMF gets converted to mycophenolic acid via a reaction by a plasma esterase)

Mycophenolic acid inhibits Inosine Monophosphate dehydrogenase (IMPDH) Type II, the rate limiting enzyme in de novo synthesis of purines

Selectively inhibits lymphocyte proliferation

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15
Q 
Mycophenolate Mofetil (MMF)
Adverse Effects
A 
Diarrhea, nausea, vomiting
Leukopenia
Anemia
Embryo/fetal toxicity - congenital abnormalities
Increased infection risk
Increased malignancy risk

Can cause appearance of PML (progressive multifocal leukoencephalopathy) - inflammatory response in brain caused by reactivation of JC virus

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16
Q 
Mycophenolate Mofetil (MMF)
Contraindications
A

Do NOT give MMF to a man or woman of child bearing age who wishes to have children

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17
Q

What are the calcineurin inhibitors?

A

Cyclosporine

Tacrolimus

18
Q

Calcineurin Inhibitors

Indications

A

Prevent solid organ rejection
Prevent GvH disease
Several autoimmune disorders (Psoriasis, RA, SKE, Inflammatory bowel)

19
Q

Cyclosporine

MOA

A

Cyclosporine binds cyclophilin, which is a peptidylprolyl isomerase, inhibiting the enzyme’s activity.

This complex inhibits Calcineurin, thus inhibiting T cell activation.

20
Q

What is the normal function of Calcineurin?

A

Signaling enzyme that activates upon an increase in intracellular Ca2+.
Dephosphorylates inactive NFAT and activates it, activating expression of IL-2 for T cell survival

21
Q

Tacrolimus

MOA

A

Tacrolimus binds to FKBP (FK506 binding protein), a peptidylprolyl isomerase, inhibiting the enzyme’s activity.

This complex inhibits Calcineurin, thus inhibiting T cell activation.

22
Q

Calcineurin Inhibitors

Metabolism

A

Both Cyclosporine and Tacrolimus are extensively metabolized by CYP3A4

23
Q

Calcineurin Inhibitors

Adverse Effects

A

Nephrotoxicity

HTN

24
Q

What are the mTOR inhibitors?

A

Sirolimus

Everolimus

25
Q

Sirolimus and Everolimus

MOA

A

Both bind FKBP, forming a complex that inhibits the mTAR kinase complex.

Inhibits IL-2 mediated signals in T cells, thereby inhibiting T cell proliferation

26
Q

Sirolimus and Everolimus

Indications

A

Prophylactic prevention of graft rejection
Prevent GvH disease
Inhibit restenosis in coronary stents

27
Q

Sirolimus and Everolimus

Contraindiciations

A

Pregnancy

Liver and lung transplants

28
Q

What is induction therapy?

A

Using anti-lymphocytic antibodies to acutely inhibit T cell responses in the recipient at the time of transplant

Use either lymphocyte depleting antibodies or functional inhibition antibodies

29
Q

What is the difference between Lymphocyte Depleting Abs vs. Functional Inhibition Abs in Induction therapy?

A

Lymphocyte depleting Abs
Getting rid of lymphocytes that would attack the graft entirely

Functional Inhibition Abs
Inhibit the lymphocytes, but do not kill them

30
Q

Rabbit Anti-thymocyte Globulins

MOA

A

Actively depletes lymphocytes from blood and lymphoid organs

31
Q

Rabbit Anti-thymocyte Globulins

Adverse Effects

A

Cytokine release syndrome (Ab activates T cell and induces cytokines)

Leukopenia and increased infections

32
Q

Alemtuzumab

MOA

A

Anti-CD52 (attacks T, B cells, macrophages, NK cells, granulocytes)

Triggers Ab-mediated lysis of lymphocytes

33
Q

Alemtuzumab

Adverse Effects

A

Cytokine release syndrome

34
Q

Basiliximab

MOA

A

Antagonist of the IL-2 receptor, inhibiting T cell proliferation

Functional inhibitor, does not kill the lymphocytes

35
Q

When approaching immunosuppressive therapy after organ transplant, how do you design the patient’s therapy during the first post-transplant week? Beyond that?

A

Induction therapy is given intra-operatively and during the first week

Maintenance therapy begins after that, including a Glucocorticoid + Cyclosporine/Tacrolimus + Anti-proliferative drug

36
Q 
Intravenous Immunoglobulin (IVIG)
MOA
A

Purified human Ig from pooled human plasma

Prophylactically provides passive immunity to individuals with underlying immunodeficiencies

37
Q

Hyperimmune Ig

MOA

A

Similar to IVIG, but it’s purified from individuals with high titers against a specific antigen or organism

38
Q

Rho(D) Immune Globulins

MOA

A

Antibodies specific for Rh(D) antigen on RBCs

Used to prevent hemolytic disease of the newborn in Rh– women

39
Q

What are the immune checkpoint inhibitors used?

A

Ipilimumab

Pembrolizumab/Nivolumab

40
Q

Ipilimumab

MOA

A

Monoclonal Ab specific for CTLA4 protein on activated T cells

Leads to enhanced T cell activation by preventing CTLA4 from binding CD80/86 and delivering a negative signal

41
Q

Pembrolizumab and Nivolumab

MOA

A

Used in metastatic melanoma and non-small cell lung cancer

Abs specific for PD1 protein on T cells, blocking the PD1/PD1-L interaction that tumor cells use to evade the immune system

Pharmacology (67 decks)

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