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Microbiology and immunology > Immunopharmacology > Flashcards

Immunopharmacology Flashcards

1
Q

What are the classes of drugs used for immune suppression in transplantation?

A
  • Glucocorticoids (steroids)
  • Calcineurin inhibitors
  • Antimetabolites
  • IL-2 receptor monoclonal antibodies (“mabs”)
  • m-TOR (target of rapamycin) inhibitors
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2
Q

Which branch of the immune system is most affected by glucocorticoids?

A

Cell-mediated immunity

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3
Q

How do glucocorticoids function in immune suppression?

A
  • Inhibit genes that code for cytokines, most importantly IL-2
  • IL-2 is a proliferation signal for T cells, so its inhibition reduces T cell proliferation
  • Glucocorticoids also suppress B cell expression of IL-2 and IL-2 receptors
  • Anti-inflammatory effects (upregulates expression of lipocortin)
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4
Q

What are the side effects of glucocorticoids?

A
  • Immunodeficiency
  • Adrenal gland suppression (if used for over 21 days)
  • Hyperglycemia and fat redistribution (characteristic moon face)
  • Growth failure and delayed puberty
  • Excitatory effects on CNS (euphoria, psychosis)
  • Osteoporosis
  • Cataracts
  • Gastric ulcers (prevented with concurrent administration of omeprazole, misoprostol)
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5
Q

What are the calcineurin inhibitors?

A
  • Cyclosporine
  • Tacrolimus
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6
Q

What is the mechanism of action of the calcineurin inhibitors?

A
  • Inhibit calcineurin, which phosphorylates and activates NF-AT
  • NF-AT is a transcription factor involved in the synthesis of interleukins (e.g. IL-2) by activated T cells
  • Therefore, the drugs decrease levels of IL-2 synthesis
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7
Q

What are the indications of calcineurin inhibitors?

A
  • Human organ transplantation
  • GVHD after hematopoietic stem cell transplantation
  • Select autoimmune disorders
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8
Q

How are calcineurin inhibitors metabolized?

A

By P450 3A in the liver, with many drug–drug interactions

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9
Q

What are the adverse effects of calcineurin inhibitors?

A
  • Very narrow therapeutic window
    • If levels are too high: toxicities, e.g. nephrotoxicity, confusion, hyperglycemia (especially with tacrolimus), hypertension
    • If levels are too low, transplant rejection may occur
  • Increased risk of lymphoma and other cancers, e.g. Kaposi sarcoma, skin cancer, has been reported with cyclosporine (though recent evidence suggests this isn’t true)
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10
Q

What are the parameters that must be monitored while taking cyclosporine?

A
  • Trough levels
  • Serum electrolytes
  • Kidney function
  • Liver function
  • Blood pressure
  • Serum cholesterol
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11
Q

What are the indications of cyclosporine specifically?

A
  • Ophthalmic solution is available for severe dry eye syndrome and ocular GVHD
  • Cyclosporine is combined with methotrexate to prevent GVHD after allogeneic stem cell transplantation
  • Used in a variety of autoimmune disorders, including uveitis, rheumatoid arthritis, psoriasis, and asthma
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12
Q

What are the indications of tacrolimus specifically?

A

Topical preparation is available for dermatologic diseases, e.g. atopic dermatitis, psoriasis

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13
Q

What is an example of an m-TOR inhibitor?

A

Sirolimus (rapamune)

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14
Q

What are the adverse effects of sirolimus?

A
  • Narrow therapeutic window
    • If levels are too high: toxicities, e.g. confusion, nephrotoxicity
    • If levels are too low, transplant rejection may occur
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15
Q

What is the difference between the use of antimetabolites in anticancer chemotherapy and in immune suppression?

A

In immune suppression, the dose is lower

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16
Q

What cells do antimetabolites affect?

A

B cells and T cells

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17
Q

What are examples of antimetabolites?

A
  • Methotrexate
  • Azathioprine
  • Mercaptopurine
  • Mycophenolate
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18
Q

What is methotrexate?

A

A folic acid analogue that binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate

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19
Q

What are the indications of methotrexate?

A
  • Treatment of autoimmune diseases (e.g. rheumatoid arthritis, Behçet’s disease)
  • Transplantations
20
Q

What are the indications of azathioprine and mercaptopurine?

A

Transplant and rejection reactions

21
Q

What is mycophenolate?

A

A reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH), leading to depletion of guanosine nucleotides

22
Q

What are the indications of mycophenolate?

A
  • More effective than azathioprine in preventing acute rejection
  • Used in combination with cyclosporine and prednisolone
  • Mycophenolate mofetil is used in solid organ transplant patients for refractory rejection
  • Mycophenolate mofetil is combined with prednisonse as an alternative to cyclosporine or tacrolimus in patients who do not tolerate these drugs
  • In renal transplants, it is used with low-dose cyclosporine to reduce cyclosporine-induced nephrotoxicity
23
Q

What are the components of tacrolimus-led triple therapy?

A
  • Tacrolimus (0.1 mg/kg/day) twice daily (every 12 hours)
  • Prednisolone
  • Azathioprine (1–2 mg/kg) once daily
24
Q

What organ is tacrolimus-led triple therapy used for?

A

Kidney transplants

25
Q

What are the monoclonal antibodies used in immune suppression?

A
  • Muromonab-CD3
  • Basiliximab (IL-2 receptor antagonist)
  • Daclizumab (IL-2 receptor antagonist)
  • Infliximab (anti-TNF-α)
  • Adalimumab (anti-TNF-α)
  • Rituximab (CD20 antagonist)
  • Omalizunab (anti-IgE)
  • Tocilizumab (anti-IL-6)
  • Sarilumab (IL-6 receptor antagonist)
  • Secukinumab (anti-IL-17)
26
Q

Muromonab-CD3 is a monoclonal antibody used to block CD3 used in TCR signaling. However, initial binding of the drug causes a transient cytokine release and a cytokine storm. How are the negative effects of this action mitigated?

A

Concurrent administration of glucocorticoids and other anti-inflammatory drugs (methylprednisolone, diphenydramine, acetaminophen)

27
Q

What are the indications of IL-2 receptor antagonist monoclonal antibodies

A
  • Prophylaxis of acute renal transplant rejection, in combination with cyclosporine, tacrolimus, and glucocorticoids
  • Treatment of the donor’s bone marrow before grafting
28
Q

How are the IL-2 receptor antagonist monoclonal antibodies administered?

A

IV

Basiliximab is administered as two doses: one 2 hours prior to the surgery, one 4 days after the surgery

29
Q

What is the half-life and duration of action of daclizumab?

A
  • Half-life of 20 days
  • Duration of blockade is 120 days
30
Q

What is the half-life and duration of action of basiliximab?

A

7 days

31
Q

What are the adverse effects of the anti-IL-2 monoclonal antibodies?

A
  • Generally well tolerated
  • The major toxicity is on the GI system
32
Q

What are the indications of the anti-TNF-α monoclonal antibodies?

A

T cell-dependent rheumatoid arthritis

33
Q

How are the anti-TNF-α monoclonal antibodies administered?

A

At a low dose alongside glucocorticoids to treat the flare-up of the autoimmune disease

34
Q

What are the adverse effects of the anti-TNF-α monoclonal antibodies?

A
  • Serious infections (namely tuberculosis) that may lead to death—treatment must be stopped if the patient develops a fever consistent with infection
  • Neurologic: multiple sclerosis, seizures, inflammation of the ocular nerve
  • Exacerbation of congestive heart failure
35
Q

What are the indications of rituximab?

A
  • B cell lymphoma
  • Rheumatoid arthritis with a B cell component in its pathology
36
Q

Which cytokine was most implicated in cytokine storm syndrome in COVID-19?

A

IL-6

37
Q

What are the indications of tocilizumab?

A
  • Cytokine release syndrome
  • Giant cell arteritis
  • Rheumatoid arthritis
38
Q

When in the course of COVID-19 is tocilizumab administered?

A

After the acute mild disease, when moderate to severe symptoms begin to show

39
Q

What are the indications of secukinumab?

A

Moderate-to-severe plaque psoriasis

40
Q

What conditions are immune stimulants used for?

A
  • Immunodeficiency disorders
  • Chronic infectious diseases
  • HIV/AIDS
  • Cancer
41
Q

What are the classes of immune stimulant drugs?

A
  • Anti-PD-1 antibodies: nivolumab, tremelimumab
  • Anti-CTLA-4 antibodies: ipilimumab, lambrolizumab, pidilizumab
  • Interferons
  • IL-2
42
Q

What are the uses of interferons in immune stimulation?

A
  • Antiviral (type I)
  • Anticancer
  • Immunomodulating effects (type II)
43
Q

What are the adverse effects of interferons?

A
  • Flu-like symptoms
  • Fatigue
  • Malaise
44
Q

What are the uses of IL-2 in immune stimulation?

A
  • T cell proliferation
  • NK cell activation
  • LAK cell activation
  • Treatment of malignant melanoma, renal cell carcinoma, Hodgkin disease
45
Q

What are the adverse effects of IL-2?

A
  • Fever
  • Anorexia

Microbiology and immunology (33 decks)

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