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HD > Pharmacology 2: Therapeutic Approach To Autoimmune Disorders > Flashcards

Pharmacology 2: Therapeutic Approach To Autoimmune Disorders Flashcards

1
Q

What is the major cause of morbidity and disability (1 in 30 adults in their lifetime)?

A

Autoimmune disorders.

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2
Q

How can autoimmune disorders be classified?

A

By organ involvement.

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3
Q

List 4 types of immune responses?

A

1- type 1 hypersensitivity - not associated with autoimmune disease.
2- type 2 hypersensitivity - causes injury to a single tissue or organ and is mediated by specific autoantibodies.
3- type 3 hypersensitivity - results from deposition of immune complexes which activates complement system.
4- type 4 hypersensitivity - mediated by activated T cells and macrophages.

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4
Q

The management of autoimmune diseases depends on what?

A

Organ system involved.

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5
Q

In general, the treatment of autoimmune diseases involves the use of what?

A

Immunosuppressive agents.

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6
Q

List an autoimmune condition that doesn’t require immune suppression?

A

Type-1 DM.

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7
Q

List uses of immunosuppressants?

A

1- organ transplantation.
2- autoimmune diseases.

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8
Q

List the 5 classifications of immunosuppressant drugs?

A

1- calcineurin inhibitors.
2- m-TOR inhibitors.
3- anti proliferative drugs.
4- glucocorticoids.
5- biological agents.

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9
Q

List 5 classification of biological agents?

A

1- polyclonal antibodies.
2- anti-CD3 antibody.
3- IL-2 receptor antagonists.
4- IL-1 receptor antagonist.
5- TNF alpha inhibitors.

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10
Q

List glucocorticoids?

A
  • prednisolone.
  • methylprednisolone.
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11
Q

List antiproliferative drugs?

A
  • azathioprine.
  • methotrexate.
  • cyclophosphamide.
  • chlorambucil.
  • mycophenolate mofetil.
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12
Q

List m-TOR inhibitors?

A
  • sirolimus.
  • everolimus.
  • temsirolimus.
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13
Q

List calcineurin inhibitors?

A
  • cyclosporine (ciclosporine).
  • tacrolimus.
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14
Q

List polyclonal antibodies?

A
  • antithymocyte antibody (ATG).
  • rho (D) immune globulin.
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15
Q

List anti-CD3 antibody?

A

Muromonab CD3.

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16
Q

List IL-2 receptor antagonists?

A
  • basiliiximab.
  • daclizumab.
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17
Q

List IL-1 receptor antagonist?

A

Anakinra.

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18
Q

List TNF alpha inhibitors?

A
  • etanercept.
  • infliximab.
  • adalimumab.
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19
Q

What are the most commonly used immunosuppressant drugs?

A

Glucocorticoids.

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20
Q

How do glucocorticoids act?

A

By inhibiting the production of prostaglandins, leukotrienes, histamine, bradykinin and PAF.
Diminishes chemotactic activity of neutrophils and monocytes.
Cause sequestration of lymphocytes in lymphoid tissue resulting in lymphopenia.
Inhibit IL-1 production, IL-2, INF.

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21
Q

How does continuous administration of GCs affect immunity?

A

Increases the catabolism of IgG.

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22
Q

What is the mechanism of action of glucocorticoids?

A
  • GRs reside in the cytoplasm in an inactive form.
  • Steroid binding results in receptor activation and translocation to the nucleus.
  • They interact with specific DNA sequences called GREs (Glucocorticoids Response Element).
  • Genes can be activated or inhibited by GR-GRE interactions.
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23
Q

What is the first line immunosuppressive drugs?

A

Glucocorticoids.

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24
Q

List the uses of glucocorticoids as immunosuppressives?

A

1- graft rejection.
2- graft vs host disease (GVHD).
3- rheumatoid arthritis.
4- bronchial asthma.
5- ITP.
6- myasthenia gravis.
7- rheumatic fever.
8- glomerulonephritis.
9- SLE.

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25
Q

What is the preferred route of administration of glucocorticoids?

A

Local:
- intra-articular.
- intra-bursal.
- intra-lesional.
- intra-synovial.
- soft tissue.
- intra-rectal.
- topical.
- nasal.
- inhaled.

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26
Q

What is the other route of administration of glucocorticoids?

A

Systemic:
- oral.
- IV.
- IM.
- SC.

27
Q

When do glucocorticoids show toxicity?

A

When they are used for short periods (< 2 weeks), it is unusual to see serious adverse effects even with moderately large doses.
So toxicity only seen when it is used for more than 2 weeks (so if it’s used for more than 2-3 weeks it needs to be stopped gradually to avoid HPA axis suppression).

28
Q

List AE of glucocorticoids?

A

1- HPA axis suppression: withdrawal.
2- fluid and electrolyte abnormalities.
3- hypertension.
4- hyperglycemia.
5- increases susceptibility to infection.
6- peptic ulcer.
7- osteoporosis.
8- myopathy.
9- behavioral disturbances.
10- cataracts.
11- growth arrest.
12- cushing’s habitus: characteristic habitus of steroid overdose, including fat redistribution, striae, and ecchymoses.

29
Q

How does Azathioprine work?

A

Inhibits purine biosynthesis.

30
Q

List the MOA of Azathioprine?

A
  • undergoes reduction to 6-mercaptopurine and then to 6-thioguanine.
  • this forms a false purine nucleotides, thus inhibiting DNA replication and cell proliferation.
  • also triggers apoptosis.
  • these actions results in reduction of B and T lymphocytes, reduced IL-2, IgM and IgG.
31
Q

List the adverse effects of Azathioprine?

A

Bone marrow suppression, hepatotoxicity; increased susceptibility to infection.

32
Q

Give an example of an interaction of Azathioprine? and what does it result in?

A

Concomitant use of xanthine oxidase inhibitors and Azathioprine, results in profound myelosuppression.

33
Q

How does Mycophenolate mofetil (MMF)?

A

It is an antimetabolite that inhibits purine synthesis.

34
Q

What is Mycophenolate mofetil (MMF) used in?

A

Used in treatment for SLE nephritis, other connective tissue diseases and systemic vasculitis.

35
Q

What is MOA of Mycophenolate mofetil (MMF)?

A

MMF is metabolized to mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the guanine nucleotide synthesis pathway used by lymphocytes.

36
Q

List the AE of Mycophenolate mofetil (MMF)?

A

Gastrointestinal disturbances (diarrhea is common),
Myelosuppression,
Hepatotoxicity,
Adverse lipid profile,
Increased risk of malignancy and pancreatitis.

37
Q

List calcineurin inhibitors?

A
  • cyclosporin.
  • tacrolimus.
38
Q

What is calcineurin inhibitors MOA?

A

Inhibit cytokine-driven activation and proliferation of activated T cells by interfering with synthesis of IL-2.
They bind to receptors called immunophilins (cyclophilin, and FKBP-12 respectively), and form complexes that inhibit IL-2 production via calcineurin pathway.

39
Q

Which immunophilins does cyclosporin bind to?

A

Cyclophilin.

40
Q

Which immunophilins does tacrolimus bind to?

A

FKBP-12.

41
Q

What is the old name of sirolimus?

A

Rapamycin.

42
Q

What is sirolimus (rapamycin)?

A

A macrolide antibiotic.

43
Q

What does sirolimus bind to?

A

Binds to FKBP-12.

44
Q

What is the MOA of sirolimus?

A

Binds to FKBP-12, and the complex binds to and inhibits activation of mTOR (mammalian target of rapamycin), an important signaling kinase.
This in turn suppresses cytokine-driven T-cell and B-cell proliferation and antibody production.

45
Q

What is mTOR (mammalian target of rapamycin)?

A

An important signaling kinase.

46
Q

List the 2 uses of sirolimus?

A

1- preventing rejection after solid organ transplantation.
2- autoimmune inflammatory disorders such as SLE and Behcet’s syndrome.

47
Q

What triggers rheumatic fever?

A

Triggered by an immune-mediated delayed response to infection with specific strains of group A streptococci, which have antigens that cross-react with cardiac myosin and sarcolemmal membrane proteins.

48
Q

List drugs that are used for rheumatic fever?

A

1- antibiotics (Benzathine, Benzylpenicillin).
2- aspirin; high doses (8g).
3- glucocorticoids (Prednisolone).

49
Q

Why is Benzathine added to benzylpenicillin?

A

Pen G is used as prophylaxis, so we add Benzathine to prolong its half-life (given once a month).

50
Q

List the 5 drugs used for SLE?

A

1- hydroxychloroquine (anti-malarial).
2- azathioprine or mycophenolate mofetil (MMF).
3- topical or intra-articular steroids (intra-thecaly).
4- methylprednisolone and cyclophosphamide.
5- B-cell depletion with rituximab may also be effective.

51
Q

Severe manifestations of SLE such as lupus nephritis are traditionally managed with what?

A

IV pulses of methylprednisolone and cyclophosphamide.

52
Q

What is hydroxychloroquine used for?

A

An antimalarial drug, is used commonly for mild manifestations of SLE and other connective tissue diseases.

53
Q

What is the MOA of hydroxychloroquine?

A

It can reduce the production of pro-inflammatory cytokines including TNF alpha and IL-1b.

54
Q

List the AE of hydroxychloroquine?

A

1- GI disturbances, rashes, and rarely bloody dyscrasias.
1- retinal toxicity may rarely occur with long-term use; measurement of visual acuity initially and annually.

55
Q

What is rituximab?

A

A chemical monoclonal IgG1 antibody specific for CD20, which is expressed in B cells but not plasma cells.

56
Q

How is rituximab administered?

A

IV infusion.

57
Q

What is the major AE of rituximab?

A

Increased susceptibility and infusion reactions.

58
Q

In myasthenia gravis antibodies develop against what?

A

Antibodies develop against nicotinic receptors (Nm) at the muscle endplate

59
Q

What is the treatment for myasthenia gravis?

A
  • neostigmine 15 mg orally every 6 hours.
  • corticosteroids (prednisolone).
  • other immunosuppressants: azathioprine.
    If it doesn’t work we can also do plasmapheresis.
60
Q

What drug inhibits IL-2R signaling?

A

Sirolimus.

61
Q

What drugs inhibit de novo purine synthesis?

A

Methotrexate.
Azathioprine.
Mycophenolate mofetil.

62
Q

What drugs cause cytotoxicity via DNA damage?

A

Cyclophosphamide.

63
Q

What drugs inhibit expression of TNF alpha and other cytokines?

A

Hydroxychloroquine.

64
Q

What drugs inhibit IL-2 expression?

A

Cyclosporin,
Tacrolimus.

HD (14 decks)

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