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Pharmacology > Immunosupressants > Flashcards

Immunosupressants Flashcards

1
Q

Induction Therapy for Organ Transplants

A

Depleting Agents - rATG or Alemtuzumab

Nondepleting agent - Basiliximab

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2
Q

Maintenance therapy for organ transplantation

A

prevention of acute organ rejection

  1. a calcineurin inhibitor
  2. an antimetabolite
  3. a glucocorticoid
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3
Q

General Rx for T cell mediated rejection

A

Glucocorticoid (high dose pulse followed by tapering dose)

rATG

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4
Q

General Rx for Antibody-mediated rejection

A

Glucocorticoid, high-dose pulse,
then oral taper

IVIG

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5
Q

The risk of rejection is highest after transplant, in general it is important to start with a potent anti-lymphocyte agent. There are two exceptions to this protocol, what are they?

A

Lung transplant - glucocorticoid therapy is delayed for several weeks to allow healing of the bronchial anastomosis

Liver- requires less immunosuppression therapy than other organs

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6
Q

rATG [Thymoglobulin]

A

Purified gamma globulin

bind a variety proteins on the surface of human T lymphocytes

Work by direct cytotoxicity through complement and cell mediated measures and the blockage of lymphocyte function by binding surface molecules.

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7
Q

rATG Adverse Effects

A

Common:
Fever, chills, leukopenia,
thrombocytopenia, headache

Serum sickness

infusion reaction - flu-like symptoms, cytokine release syndrome, local site reactions

infection and malignancy

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8
Q

Serum sickness

A

Type III Hypersensitivity

Rash, pruritus, fever, lymphadenopathy, hypotension

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9
Q

Alemtuzumab

A

Anti-CD52 monoclonal antibody

induces direct antibody dependent cellular cytotoxicity and complement-mediated lysis

Causes depletion of T and B cells

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10
Q

Adverse Effects of Alemtuzumab

A

Common - nausea, vomiting, diarrhea, headache and insomnia

Autoimmune - hemolytic anemia, thrombocytopenia, antiglomerular basement membrane disease

infusion reaction - flu-like symptoms, cytokine release syndrome, local site reactions

Infection and Malignancy

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11
Q

Baxiliximab

A

Anti-IL2Rα (anti-CD-25) Antibodies - binds the IL-2R of T cells preventing T cell activation and proliferation

Used with glucocorticoid and cyclosporine for induction therapy for renal, heart, liver, and lung transplants

2 doses on day 0 and day 4

also used refractory for acute GVHD

potential toxicities - anaphylaxis, infections, lymphoproliferative disorder (EBV+)

There is no cytokine release syndrome or drug interactions

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12
Q

Glucocorticoids

A

Prednisone, Prednisolone, Methylprednisolone, Dexamethasone

Binds to nuclear elements causing transrepression or transactivation of genes

broad anti-inflammatory effects - inhibition of prostaglandin and lipoxygenase synthesis, inhibition of T cell proliferation, humoral immunity dampened but not to a significant degree

↓ IL-1; IL-6; IL-2

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13
Q

Therapeutic Uses of Glucocorticoids

A

Prevention of transplant rejection - induction and maintenance of allograft, Acute Transplant Rejection

GVHD prevention and treatment

management of cytokine release syndrome and infusion reactions

suppression of other immunologically mediated disorders

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14
Q

Adverse Effects of Glucocorticoids

A

Impaired immunity, increased risk of infection, delayed wound healing, hyperglycemia, increased plasma cholesterol, increased BP and salt retention

Delayed effects - peptic ulcers, cushing effects (mood face, nuchal fat, weight gain, muscle wasting and osteoporosis, hirsuitism, cataracts)

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15
Q

Calcineurin Inhibitors

A

Cyclosporine - t½ 10-27 hrs
Tacrolimus - t½ 3-40 hrs

Oral, IV, high protein binding and substrates of CYP3A4 and p-glycoprotein

Requires monitoring plasma concentrations

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16
Q

Uses of Cyclosporine / Tacrolimus

A

High efficacy - prophylaxis of solid organ allograft rejection

treatment of GVHD after bone marrow transplant

also - inflammatory diseases, cyclosporine can be used as ophthalmic drops for uveitis and tacrolimus can be used topically for atopic dermatitis or psoriasis

17
Q

Which calcineurin inhibitor has become the preferred agent and why?

A

decreased acute rejection rates - more potent and better efficacy

better tolerated

18
Q

Toxicities of calcineurin inhibitors

A

Nephrotoxicity - vasoconstriction of afferent renal arteriole and interstitial fibrosis of parenchyma

Hypertension

neurotoxicity - tremor, paresthesia, headache, confusion and seizures

hepatoxicity

hyperglycemia - risk for DM with concurrent glucocorticoid use

hyperkalemia, diarrhea, nausea, vomiting

infection and malignancy

cyclosporine specific - hyperuricemia, hyperlipidemia, gum hyperplasia and hirsuitism

19
Q

Calcineurin Inhibitors: Drug Interactions

A

High potential for drug interactions - interacts with CYP3A4 and P-glycoprotein inducers or inhibitors

With any drug that also causes nephrotoxicity, neurotoxicity

These drugs are not used together

20
Q

CYP3A4 Inducers

A
  • Carbamazepine
  • Phenobarbital
  • Phenytoin
  • Rifampin
  • Efavirenz
  • St. John’s wort
21
Q

CYP3A4 Inhibitors

A
  • Verapamil, diltiazem
  • Azole antifungals
  • Macrolide antibiotics
  • Dexamethasone
  • HIV and HCV protease inhibitors
  • Grapefruit juice (CYP3A4 and P-glycoprotein)
22
Q

Cyclosporine + sirolimus

A

sirolimus must be administured 4 hours after cyclosporin

sirolimus aggravates cyclosporin-induced renal dysfuction

cyclosporin causes increased sirolimus concentration which enhances sirolimus incduced anemia, leukopenia, thrombocyptopenia, hypokalemia and diarrhea

23
Q

Tacrolimus + sirolimus

A

DO NOT GIVE TOGETHER

They enhance the toxic effects of eachother

Sirolimus decreased serum concentrations of tacrolimus

24
Q

Mycophenolate mofetil

A

Antimetabolites - Oral, IV prodrug > converted to mycophenolic acid

hepatic glucoronidation with renal excretion, half life 17 hrs

MOA - selective, uncompetitive, reversible inosine monophosphate dehydrogenase inhibition which further inhibits guanine synthesis trapping the cell in G1-S phase leading to apoptosis

Decreases lymphocyte function and T cell mediated and B cell proliferation and function

25
Q

Therapeutic uses of Mycophenolate mofetil

A

Prophylaxis of organ rejection - renal, cardiac, hepatic

used in combination with calcineurin inhibitor and glucocorticoid

largely replaced azathioprine in prophylaxis

Prophylaxis / treatment GVHD

Treatment of psoriasis, lupus, myasthenia gravis etc

26
Q

Toxicities of mycophenolate mofetil

A 
Leukopenia 
pure red cell aplasia 
increased infection and malignancy risk 
diarrhea, nausea and vomiting 
teratogenic

antacids and cholestyramine impair absorption

probenecid and some antiviral agents compete for tubular secretion

any drug with additive toxicities

27
Q

Azathioprine

A

antimetabolite Oral Prodrug

metabolized to 6-mercaptopurine

metabolized by xanthine oxidase and thiopurine methyltransferase with renal excretion

TPMT def - life-threatening myelosuppression

t1/2 of AZA ~10 minutes; t1/2 of 6-MP ~1 hour

toxic metabolites inhibits de novo purine synthesis

6-TGTP is incorporated into DNA of proliferating cells and induces strand breaks and base mispairing

28
Q

Therapeutic Uses of Azathioprine

A

Prophylaxis of organ rejection - combination with calcineurin inhibitor + AZA + glucocorticoid

RA

IBS

Acute glomerulonephritis

29
Q

Azathioprine Toxicities / Drug Interactions

A

Major effects are bone marrow suppression (leukopenia) and hepatoxicity

increased infection and malignancy risk

acute pancreatitis

skin rashes, diarrhea, nausea, vomiting

safe in pregnancy

30
Q

Azathioprine Drug Interactions

A

Allopurinol / Febuxostat
(Xanthine oxidase inhibitors)

↓ AZA inactivation&raquo_space;> shunt AZA to HGPRT pathway&raquo_space;>
Increased AZA toxicity

31
Q

Belatacept

A

Selective T cell Costimulation Blocker

CTLA4 analog that binds CD80/86 and inhibits T cell activation, cytokine production and proliferation

Used for Induction and maintenance therapy / prophylaxis of acute organ rejection in kidney transplant patients who are seropositive for EBV

combination therapy - basiliximab, mycophenolate and corticosteroids

Adverse effects are post-transplant lymphoproliferative disorders (EBV infection) or progressive multifocal leukoencephalopathy (JC virus)

32
Q

Sirolimus / Everolimus

A

mTOR Inhibitors - Oral, low bioavailability, required serum level monitoring

p-glycoprotein, CYP3A4 with fecal excretion

causes cell cycle arrest in G1 phase and inhibition of cell growth, proliferation, angiogenesis, and metabolism

drug complexes with FK-binding protein and mTOR

33
Q

Therapeutic Uses of mTOR Inhibitors

A

Sirolimus / Everolimus

Renal transplant – along with reduced-dose calcineurin inhibitor and glucocorticoids

CNI-sparing regimen: Cyclosporine-tapering after 4-8 weeks only (for pts with little risk)

cardiac and lung transplantation – delay treatment until surgical wounds heal

prevention and treatment of GVHD

Used in drug-eluting coronary stents to inhibit cell proliferation and blood cell occlusion

but not hepatic transplants - increased mortality

34
Q

Sirolimus Toxicities

A

Profound myelosuppression - thrombocytopenia, anemia and leukopenia

-impaired wound healing and dehiscence

hepatotoxicity - fatal haptic necrosis

increases TAGs and cholesterol

Peripheral edema, lymphedema, pleural effusion, pericardial effusions; pneuomonitis

Diarrhea, nausea, vomiting; headache; arthralgia; aphthous ulcers; acne

35
Q

Sirolimus Drug Interactions

A

CYP3A4 / P-gp inducers / inhibitors

when used with calcineurin inhibitor > renal deterioration, hyperTAGs, hemolytic uremic syndrome and increase in sirolimus concentration

Tacrolimus + Sirolimus competition at CYP3A4, P-gp

Pharmacology (23 decks)

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