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IHO 5 > Immunosuppressive Drugs > Flashcards

Immunosuppressive Drugs Flashcards

1
Q

Immunosuppressive therapy

A
  • Drugs that will affect multiple mediator pathways to affect inflammation and/or specific immunity.
  • Used in organ transplants, autoimmune disease and hypersensitivity
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2
Q

Gen. principles of immunosuppression

A
  • Primary immune responses more effectively suppressed than secondary immune responses.
  • Effect of drugs not the same on all immune responses
  • Immune response more likely to be INHIBITED if therapy begun before immunogen
  • Suppress the immune response to prevent immune mediated tissue damage
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3
Q

Limitations of immunosuppressive therapy

A
  • Increased risk of all types of infections

- Increased risk of lymphomas and related malignancies

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4
Q

Major classes of immunosuppressive drugs

A
  • Glucocorticoids
  • Calcineurin inhibitors
  • Antiproliferative/antimetabolic drugs
  • Antibodies
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5
Q

Primary uses of immunosuppression

A

Autoimmune diseae

  • Transplants
  • Hemolytic anemia in newborns
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6
Q

Drug of choice for autoimmune diseases, idopathic thrombocytopenic purpura, autoimmune hemolytic anemia, acute glomerulonephritis, acquired factor XIII antibodies, autoreactive tissue disorders

A

Prednisone. Response is usually good

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7
Q

Drugs of choice for organ transplant (renal and heart)

A
  • Cyclosporine
  • Prednisone
  • ALG
  • OKT3
  • monoclonal antibody
  • Tacrolimus
  • Basiliximab
  • Daclizumab
  • Sirolimus
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8
Q

Best drugs for liver transplant

A
  • Cyclosporine
  • Prednisone
  • Tacrolimus
  • Sirolimus
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9
Q

Best drugs for bone marrow suppression

A
  • Cyclosporine
  • Prednisone
  • ALC
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10
Q

What 2 classes of steroids does the adrenal cortex synthesize?

A

Corticosteroids (glucocorticoids and mineralcorticoids) (21 carbons)
Androgens (19 carbons)

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11
Q

Glucocorticoid activity

A

Carbohydrate metabolism regulating activity

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12
Q

Mineralcorticoid activity

A

Electrolyte balancing activity

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13
Q

Main glucocorticoid

A

Hydrocortisone (cortisol)

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14
Q

Main mineralcorticoid

A

Aldosterone

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15
Q

What are corticosteroids secreted in response to?

A

ACTH (Adrenocorticotropic hormone)

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16
Q

Endogenous corticosteroids

A

Varying degrees of both mineralcorticoid and glucocorticoid activity.

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17
Q

Physiologic effects of corticosteroids

A

Regulation of intermediary metabolism, CV function, growth and immunity

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18
Q

Do mineralcorticoids or glucocorticoids cause sodium retention?

A

Mineralcorticoids

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19
Q

Do mineralcorticoids or glucocorticoids cause liver glycogen deposition?

A

Glucocorticoids

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20
Q

Are mineralcorticoids and glucocorticoids cause anti-inflammatory?

A

Glucocorticoids

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21
Q

Sodium retention

A

Ability of steroid to reduce Na+ excretion by kidney in an adrenalectomized animals

22
Q

Liver glycogen deposition

A

Ability of steroid to cause hepatic deposition of glycogen in fasted adrenalectomized animal.

23
Q

Liver glycogen deposition, anti-inflammatory activity, and involution of lymhoid tissue activity do what?

A

Parallel each other

24
Q

Synthetic steroids that are used as anti-inflammatory drugs

A
  • Betamethasone
  • Dexamethasone
  • Methylprednisolone
  • Prednisone
25
Q

Duration of cortisol (hydrocortisone)

A

Short half-life (8-12 hrs)

26
Q

Betamethasone and dexamethasone half-life

A

Long (36-72 hrs)

27
Q

Methylprednisolone and prednisone half-life

A

Intermediate (12-36 hrs)

28
Q

Inhaled glucocorticoids distribution and elimination

A
  • Enhanced uptake and prolonged tissue binding in airway
  • Nearly complete hepatic first pass inactivation
  • Some systemic absorption
  • Metabolized in liver and excreted by kidney
29
Q

Glucocorticoid administration, distribution, elimination

A
  • Oral, Parenternal, Topical
  • Some systemic absorption
  • Metabolized in liver and excreted by kidney
30
Q

What protein products are responsible for the immunosuppressive effects of steroids?

A

Many different protein products

31
Q

Glucocorticoids/Anti-inflammatory steroid neutrophil action effects

A
  • more neutrophils circulating
  • accelerated release from bone marrow
  • 1/2 time in circulation increased
  • decrease in adherence capabilities (blockage of neutrophil migration into inflammatory sites
32
Q

Glucocorticoids/Anti-inflammatory steroid lymphocyte action effects

A
  • profound transient lymphopenia

- cells not lysed–move to extravascular compartments like spleen, thoracic duct, lymph nodes, bone marow

33
Q

Glucocorticoids/Anti-inflammatory steroid monocyte/eosinophil action effects

A

-decreased in peripheral blood

34
Q

Glucocorticoids/Anti-inflammatory steroid effects on synthesis and/or release of inflammatory mediators

A
  • reduce COX2 expression
  • inhibit arachidonic acid release from phospholipids–>affectin prostaglandin and leukotriene formation
  • inhibit mast cell and basophil degranulation
  • inhibit snthesis and release of TNF (cachectin), IL-1, IL-2, IFN
35
Q

Use of glucocorticoids in anti-inflammatory therapy

A
  • prevent or supress: redness, swelling, heat and pain.

- inflammation suppressed, but underlying cause of disease remains

36
Q

What can occur with systemic administration of glucocorticoids?

A
  • side effects more common–can be life-threatening

- host resistance to microbial and fungal infections lowered

37
Q

Therapeutic principles of glucocorticoids?

A
  1. Doses must be determined by trial and error and be re-evaluated.
  2. Single dose virtually w/o harmful effects
  3. Few days likely harmless, unless extreme doses
  4. Prolonged therapy increases risk of potentially lethal side effects.
  5. Treating only the symptoms
  6. Adrenal insufficiency may occur w/abrupt cessation of prolonged high-dose therapy.
38
Q

Glucocorticoid toxicity (from continued use of large doses)

A
  • Primarily associated w/systemic administration
  • Increased susceptibility to infection (immune suppression)
  • peptic ulceration
  • behavioral disturbances
  • cataracts
  • osteoporosis and vertebral compression fractures
  • inhibition of growth
39
Q

Glucocorticoid toxicity (from withdrawal or discontinuation of long-term use)

A
  • reflect symptoms of acute adrenal insufficiency
  • fever
  • myalgia
  • arthralgia
  • malaise
  • death can occur with hypotension and shock
40
Q

Calcineurin inhibitors

A

Cyclosporine

Tacrolimus (FK 506)

41
Q

Cyclosporine

A
  • Binds cyclophilin–>inhibits calcineurin activity
  • Blocks dephosphorylation events needed for cytokine gene expression and T cell activation
  • metabolized in liver
  • potential for drug interactions
  • long term therapy for transplants
  • major adverse effect: renal toxicity (must be distinguished from graft rejection in kidney transplants!) Nephrotoxicity can occur in up to 75% of patients
42
Q

Tacrolimus

A
  • Binds FKBP (FK506 binding protein)–>inhibits calcineurin activity
  • Blocks dephosphorylation events needed for cytokine gene expression and T cell activation
  • 100x more potent than cyclosporine
  • nephrotoxicity (similar adverse effects to cyclosporine)
43
Q

Function of antiproliferative/antimetabolic drugs

A

Prevent clonal expansion of both B and T lymphocytes

44
Q

Antiproliferative/antimetabolic drugs

A

Sirolimus

Mycophenolate mofetil

45
Q

Sirolumus

A
  • used in combo therapy for organ transplant rejection
  • Binds FKBP to inhibit mTOR. Blocks cell cycle progression from G1 to S phase
  • Dose dependent increase in cholesterol and triglycerides. Nephrotoxicity when in combination with cyclosporine. Increased lymphoma and infection risk.
  • Potential for drug interactions (substrate for cyp3A4)
46
Q

Mycophenolate mofetil

A
  • used in organ transplants
  • Metabolite is an inhibitor of IMPDH (needed for guanine nucleotide synthesis). B cells and T cells highly dependent on this pathway.
  • Toxicity: hematologic and GI. Leukopenia, diarrhea, vomiting.
47
Q

Relationship between immunosuppressive therapy and cancer chemo

A

Overlap occurs between drugs for immunosuppression and cancer treatment drugs

48
Q

Antibodies

A

Anti-thymocyte globulin (ATG)
Muromonab-CD3
Daclizumab
Basiliximab

49
Q

Anti-thymocyte globulin (ATG)

A
  • Prepared from hyperimmune syrum following immunization with human thymocytes
  • IG binds thymocytes in circulation–>causes lymphopenia and impaired T cell immune response
  • Toxicty: primarily ue to Ig being recognized as foreign resulting in serum sickness and nephritis. Anaphylaxis rare
50
Q

Muromonab-CD3

A
  • Used to prevent acute rejection of transplants
  • Mouse Ab binds to CD3 glycoprotein–> T cell receptor complex internalized and prevents further antigen recognition
  • Initial interaction with T cells leads to cytokine release by activating T cells (Cytokine release syndrome)–administration of glucocorticoids before admin reduces symptoms
  • Repeated use contraindicated (immune response occure to mouse Ab)
51
Q

Daclizumab or basiliximab

A
  • Anti-IL2 receptor (Anti-CD25) Ab, humanized in part
  • Used in organ transplants
  • Bind IL-2 receptor present on activatied, not resting T cells and block IL-2 mediated T cell activation events.
  • Toxicity: NO cytokine release syndrome. Lower incidence of lymphoproliferative disorders and opportunistic infections than many other immunosuppressive drugs. Anaphylactic reactions can occur.

IHO 5 (5 decks)

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