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Pharmacology (Winter) > Autoimmune Drugs > Flashcards

Autoimmune Drugs Flashcards

1
Q

What is the difference b/t Autograft, Allograft & Xenograft for organ/tissue transplantation?

A

Autograft - from 1 self
ex: babies cord blood cells to be potentially used later

Allograft - w/in the same species
ex: organ transplant, blood translocation

Xenograft - from 1 species to another

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2
Q

What are the graft (organ) rejection timelines?

A

Hyperacute
- in minutes

Acute
- 7 to 21 days

Chronic
- 3 months

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3
Q

GvHD vs organ transplantation:

A

GvHD: the donated tissue in the recipient’s body is viewed as foreign, but the donated cells/bone marrow attack the body.

Organ rejection: the donated tissue in the recipient’s body is viewed as foreign, but the recipient’s body attacks the tissue

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4
Q

What are Anti-rejection drugs?

A
  • The success of organ transplantation is due largely to the availability of effective immunosuppressive agents
  • All current anti-rejection drugs target T-cell and B-cell activation/clonal expansion, cytokine production or antibody action
  • Knowledge of the elements of immune system is essential to understanding the mechanism of actions of anti-rejection drugs
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5
Q

What is the specific immunity against organ transplantation?

A

Foreign organ proteins –> macrophages or other APC –> Th-cell & B cell –> antibodies –> neutralization, opsonization, phagocytosis –> organ rejection

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6
Q

Drugs that act on the induction phase of immune response:

A

Inhibitors of interleukin-2 production
- Cyclosporine, Tacrolimus, Myriocin/Fingolimod

Inhibitor of cytokine gene expression
- Glucocorticoids

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7
Q

What is Cyclosporine?

A
  • A fat soluble cyclic peptide with 11 amino acids derived from fungus Tolypocladium inflatum
  • Extensively used in the treatment of organ transplantation (kidney, heart, bone marrow)
  • Low doses have also proved useful in autoimmune diseases (rheumatoid arthritis)
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8
Q

What is Cyclosporines MOA?

A

o Antigen-MHC II complex binds to TH-2 cell receptorà­Ca intracellular

o Ca++/calmodulin complex stimulates phosphatase called CALCINEURIN –> ­INCREASE activation of transcription factor (NF-AT) –> INCREASE­ IL-2 gene transcription
- Cyclosporine binds to cytosolic protein, CYCLOPHILIN (immunophilin)
- CYCLOSPORINE-CYCLOPHILIN complex inhibits calcineurin/NF-AT activation and blocks IL-2 gene transcription

Decreases activation of T cells
- Inhibit IL-2 release
- DECREASE expression of IL-2 receptors
- Reduce function of the effector T cells that mediate cell mediated response
- Reduction of T cell-dependent B cell response

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9
Q

What are the Cyclosporine pharmacokinetics?

A

o Given orally or intravenously
o Oral absorption is slow and incomplete
o Metabolism occurs in both the GI and liver oPlasmahalf-life approx24hours
o Cyclosporine is concentrated in peripheral tissue (lymphomyeloid and adipose tissue)

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10
Q

What are the Cyclosporine AE’s?

A

o NEPHROTOXICITY
o Hypertension
o Increase risk of infection
o Liver dysfunction
- Regular blood level monitoring to avoid kidney
and liver toxicity
o Others: hyperglycemia, anorexia, lethargy, hirsutism, tremor, paraesthesia, gum hypertrophy, GI upset

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11
Q

What are the Cyclosporine DI’s?

A

Drugs that inhibit CsA metabolism
- Calcium channel blockers
- Antifungal agents - ketoconazole, fluconazole
- Antibacterial agents - erythromycin, clarithromycin
- Grapefruit juice

Drugs that induce CsA metabolism
- Anticonvulsants - phenytoin
- Antituberculosis agents - isoniazid, rifampin

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12
Q

What is Tacrolimus?

A

o Macrolide antibiotic produced by Streptomyces tsukubaensis
o Mechanism of action SIMILAR to cyclosporine
o At cellular level, it binds to the immunophilin FK binding protein (FKBP) which inhibits CALCINEURIN phosphatase –> DECREASE activation of transcription factor (NF-AT) –> DECREASE IL-2 gene transcription

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13
Q

What is Tacrolimus pharmacokinetics?

A

o Tacrolimus is given orally or intravenously
o Plasma half-life: 9-12 hrs
o Metabolized by the liver (99 %)
o Active in preventing organ transplant rejection
o Toxic effects similar to cyclosporine

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14
Q

What is Myriocin/Fingolimod?

A

Also known as the antibiotic ISP-1 (or thermozymocidin)
- Atypical amino acid derived from thermophilic fungi – Mycelia sterilia
- Potent inhibitor of serine palmitoyltransferase involved in sphingosine biosynthesis
– Can deplete cells of sphingolipids
- Inhibits IL-2 production – 10-100-fold more potent
than cyclosporine
Also used in the treatment of relapsing forms of multiple sclerosis (MS) in adults – sequester B/T cells in lymph nodes to prevent demyelination

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15
Q

What are Myriocin/Fingolimod AE’s?

A
  • Increased risk of serious, life-threatening infections, including progressive multifocal leukoencephalopathy (PML), a rare brain infection.
  • Vision problems
  • Swelling and narrowing of the blood vessels in the
    brain
  • Liver damage
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16
Q

Drugs acting on the effector phase of immune response:

A

Inhibit action of interleukin 2:
- Sirolimus

Inhibitors of purine synthesis:
- Myclophenolate mofetil, Azathioprine

Alkylating cytotoxic agents:
- Cyclophosphamide

Suppressor of immune response:
- Glucocorticoids

Immunosuppressive antibodies:
- Polyclonal and Monoclonal antibodies

Others:

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17
Q

What is Sirolimus?

A

o New macrolide antibiotic derived from Streptomyces hygroscopicus
o Binds to intracellular immunophilins but DOES NOT block IL-2 gene transcription
o Interferes with IL-2 signal transduction pathway in activated T cells
o Result: decreased clonal proliferation of T- cells and B-cells

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18
Q

What is Sirolimus MOA?

A

Inhibition of IL-2 mediated gene activation

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19
Q

What is Mycophenolate Mofetil?

A

o Converted to mycophenolic acid oSelectively inhibit proliferation of both T
and B lymphocytes, and cytotoxic T cells
o Mechanism of action: Potent inhibitor of inosine 5’-mono-phosphate dehydrogenase – a crucial enzyme in purine synthesis
o T-cells and B cells are particularly dependent on this pathway for proliferation

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20
Q

What is Mycophenolate Mofetil pharmacokinetics?

A

o Oral administration (well absorbed)
o Magnesium and aluminum impair absorption
o Metabolite mycophenolic acid and glucuronide conjugate undergoes enterohepatic circulation
o Eliminated by kidney as inactive glucuronide
o Indicated in transplant recipients with cyclosporine and steroids

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21
Q

What is Azathioprine?

A

o Metabolized to 6-mercaptopurine which is a purine antimetabolite – remember anti-cancer drugs
o Interferes with purine synthesis (inhibits HGPRT enzyme – catalyzes conversion of purine base to purine ribosyl monophosphate). Cytotoxic on dividing cells.
o Inhibit clonal T-cell and B-cell proliferation of immune response
o Inhibits both cell mediated and antibody mediated immune reactions

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22
Q

What is Azathioprine Clinical Indications?

A

o Intravenous loading dose on day of transplantation
o Oral dosing for maintenance
o Clinically used in combination with other
immunosuppressant drugs
- Kidney, liver transplants
- Rheumatoid arthritis
o Major side effect: bone marrow depression

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23
Q

What is Cyclophosphamide?

A

o A nitrogen mustard, an alkylating agent
o Orally absorbed. Plasma T1/2 = 6.5 hours
o Inactive until metabolized by the liver into the active phosphoramide mustard
o Alkyl groups cross-react with two DNA nucleophilic sites (intra/inter guanine) –> inhibit DNA replication
o Results in subsequent cell death (apoptosis) o Used for treatment of Lupus and RA

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24
Q

What is Cyclophosphamide AE’s?

A

o Pronounced effect on lymphocytes
o Adverse effects:
- Bone marrow depression. Affects more white blood cells than platelets
- GI disturbance
o Toxic metabolite acrolein
- Hemorrhagic cystitis

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25
Q

What are Glucocorticoids?

A

o Prednisone, methylprednisolone, dexamethasone
o High doses induce lymphocyte migration to extravascular space - subsequently reduce lymphocyte proliferation
o Size reduction of lymphoid tissues o Affect more T cells than B cells

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26
Q

What is the Glucocorticoids MOA?

A

Suppress the induction and effector phases of immune response
- Inhibit macrophage activation (antigen presenting cell) and release of IL-1β
- Decrease clonal expansion of T and B cells and IL-2 secreting T cells
- Decrease production and action of cytokines (interleukins, TNFg)
- Decrease generation of IgG

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27
Q

What are the Glucocorticoids Clinical Uses?

A

o Anti-inflammatory and immunosuppressive therapy
- Asthma, allergic rhinitis, eczema, severe drug allergic reaction, rheumatoid arthritis, organ transplant
o Neoplastic diseases
- Hodgkin’s disease, acute lymphocytic leukemia
o Replacement therapy
- Addison’s syndrome (autoimmune polyendocrine syndrome)

28
Q

What are the Glucocorticoids AE’s?

A

o Insomnia and mood changes
- Cause unknown. Take it in the morning
o Increased appetite and weight gain
o Suppress response to injury or infection
o Metabolic effects
- Fluid retention. Na+ retention and K+ depletion
- Osteoporosis
- GI bleeding
- Hyperglycemia

29
Q

What are Immunosuppresive Antibodies?

A

Antibodies against human lymphocytes or their surface receptors have significant immunosuppressant actions
o Polyclonal antibodies
- Anti-lymphocyte immunoglobulin
– Inhibits T-cells. Lysis
o Monoclonal antibodies
- Antibodies against interleukin 2 receptors
– Prevents T-cell and B-cell activation and proliferation

30
Q

What are Polyclonal Antibodies?

A

o Thymoglobulin
- AKA rabbit-derived anti-thymocyte globulin (RATG)
o Bind to proteins on the surface of lymphocytes triggering the complement response –> Lysis of lymphocytes
o Indiscriminate action on all T cells
o Adverse effects: newly synthesized antibodies against these polyclonal antibodies could produce anaphylactic reactions

31
Q

What are Monoclonal Antibodies?

A

o Directly against a specific surface component of T cells
o Affects the induction and effector phases of immune response to allograft.
o Targets:
- CD3 proteins with antigen receptors
- CD4 co-receptors
- IL-2 receptors
- TNFa, a pro-inflammatory cytokine
– Infliximab – chimeric human/mouse monoclonal antibody directed to TNF-a

32
Q

Reduction of induction phase of immune response:

A

Inhibitors of interleukin-2 production:
- Cyclosporine, Tacrolimus
Inhibitor of cytokine gene expression:
- Glucocorticoids (also effector)
Immunosuppressive antibodies:
- Monoclonal

33
Q

Reduction of effector phase of immune response:

A

Inhibitor of interleukin-2 action:
- Sirolimus
Inhibitors of purine synthesis:
- Mycophenolate mofetil, Azathioprine
Alkylating – cytotoxic mechanisms:
- Cyclophosphamide
Immunosuppressive antibodies:
- Polyclonal and Monoclonal antibodies

34
Q

Prevention of Acute Rejection:

A
  • High dose glucocorticoids, purine synthesis inhibitors, immunosuppressive antibodies
  • 1-2 wks prior to transplant
35
Q

Prevention of Chronic Rejection:

A

Triple drug therapy consisting of low dose
- Calcinurin inhibitor (CsA, Tacrilomus)
- Inhibitor of purine synthesis (Mycophenolate, Azothioprine)
- Glucocorticoid
- Breakthrough Episodes in Chronic Rejection (GVHD):

Alkylating – cytotoxic mechanisms:
- Cyclophosphamide

Immunosuppressive antibodies:
- Polyclonal and Monoclonal antibodies
– RATG
– CD3
– CD4
– IL-2R
– TNFa (Infliximab )

36
Q

Autoimmune diseases:

A

Occurs when the adaptive immune system loses self-tolerance rendering the system unable to distinguish between self and non-self antigens

In the US, >23.5 million people are affected by at least one autoimmune disease, 75% of those affected are women.

37
Q

What is Self-Tolerance?

A

The immune system protects itself against autoreactive B and T cells via primary and peripheral tolerance.

In central tolerance, negative selection results in the clonal deletion of immature lymphocytes in the bone marrow (B cells) and thymus (T cells) that recognize self-antigens with high affinity.

In peripheral tolerance (beyond the lymphoid organs), mature autoreactive lymphocytes are inactivated or killed by mechanisms including anergy, immunological ignorance/antigen sequestration, programmed cell death (PCD) or suppression by regulatory T cells (Tregs).

38
Q

Loss of Self-tolerance:

A

When these self-tolerance mechanisms fail, the adaptive immune system responds as it would to non-self antigens and mounts an immune response. The body’s inability to eliminate the self-antigen results in a sustained response that leads to chronic inflammation.

Autoreactive T helper 1 (Th1) cells release interferon (IFN)γ and interleukin (IL)-17 to activate macrophages that secrete additional cytokines (such as tumor necrosis factor (TNF) or IL-1) to cause local inflammation.
-Autoreactive cytotoxic T (Tc) cells cause extensive tissue damage.
-Inappropriate T cell responses help autoreactive B cells initiate polyclonal activation and the generation of harmful autoantibodies.
-Autoantibodies activate the complement system to cause inflammation, bind receptors to block hormone and neurotransmitter signals, or react with antigens in the blood to form complexes.
-Autoimmunity is a natural consequence that arises from the necessity of generating lymphocytes capable of recognizing any antigen. Clonal deletion in central tolerance, typically via apoptosis, is therefore an essential component of safeguarding against autoreactive lymphocytes.

39
Q

Causes of loss of Self-tolerance:

A

-Viral infection of a tissue can activate non-virus-specific T cells
-‘Molecular mimicry’ - microbial antigens share epitopes similar to human self- proteins and induce an inflammatory response against the self-antigen
-Immune cells targeting tumours may become or remain active and target healthy cells. Similarly, ‘immunoediting’ theory suggests that antigens derived from cancer cells containing somatic mutations induce an adaptive immune response and generate cross-reactivity against native proteins.
-Damage-associated molecular patterns (DAMPs) (molecules released from stressed or injured cells that act as danger signals to alert the immune system) may trigger autoimmunity. Nucleic acids released from dying cells can stimulate toll-like receptors (TLRs) on B cells and promote autoantibody generation.

40
Q

Drugs Used in RA Therapy:

A

o NSAIDs
o Glucocorticoids

o Disease-Modifying Antirheumatic Drugs (DMARDs)
- Methotrexate
- Sulfasalazine
- Leflunomide
- Anti-TNFa therapies
- Anti – IL therapies

41
Q

Rheumatoid Arthritis:

A

Chronic Autoimmune Disorder
*Initiation Phase – inflammation within joint
*Amplification phase – T cell activation
*Chronic inflammatory phase – tissue injury due to destruction of bone and remodeling of joint

42
Q

Why are Anti-TNF and Anti-IL effective DMARDs?

A

Are released within joint during chronic inflammatory phase

Are early participants in the inflammatory cascade

43
Q

Anti-TNF based therapeutics:

A

Entanercept
- soluble receptor TNF antagonist
- Dimeric fusion protein that binds TNF

44
Q

What is Etanercept?

A
  • Only soluble receptor TNF antagonist
  • Fully human protein
  • Binds TNF, soluble and
    cell bound
  • No neutralizing antibodies; low immunogenicity
  • Does not bind complement; no cell lysis
45
Q

Anti-TNF based therapeutics ex’s:

A

o Entanercept
- soluble receptor TNF antagonist
- Dimeric fusion protein that binds TNF
o Infliximab
o Adalimumab
o Certolizumab
o Golimumab

(last 4 are Monoclonal antibody that binds TNF -complement-mediated cell lysis)

46
Q

Anti-IL based therapeutics:

A

o Anakinra
o Canakinumab
o Tocilizumab
o Rituximab

47
Q

Anakinra:

A

-mimics IL-1 receptor antagonist (IL-1Ra)

48
Q

Tocilizumab:

A

IL-6 receptor antagonizing antibody

49
Q

Rituximab:

A

B-cell lysis by complement dependent cytotoxicity (CDC) & antibody dependent cell mediated cytotoxicity

50
Q

Ulcerative Colitis:

A

oInflammation of the submucosa- oUlcerations that may cover the entire
surface of the colon
oDiarrhea, bleeding, severe pain
oLoss of nutrition, anemia-starvation is a risk
oColon can become “stiff” from scarring, and burst, leading to peritonitis

51
Q

Crohn’s disease:

A

oInflammatory disease which can cover the entire digestive system
oTends to be separate, isolated regions of inflammation
oUnlike UC, fistulas may form oUnlike UC, the intestinal wall may be
breached
oCD may also be associated with severe skin inflammation

52
Q

IBD (IBS):

A

oThere is no cure, only treatments which are variably effective
oSurgical removal of the colon can eliminate UC, but surgery cannot always eliminate CD
oThese are typical relapsing/remitting inflammatory diseases (e.g. R. Arthritis, MS,

53
Q

Three goals to treatment for UC & CD:

A

1- Treat the acute outbreak
2-Induce and retain remission
3-Treat complications

54
Q

5-ASA (mesalamine)- Based Therapy:

A

o5-Amino Salycilic acid: first-line treatment oMild to moderate UC. It is less useful in
severe UC and in CD.
oDoes NOT work by COX inhibition (NSAIDS exacerbate the disease)-
oUnknown method of action oResponse rate of 60-80%
oBut…5ASA is only released in Large Intestine via sulfasalzine

55
Q

Sulfasalazine:

A

o5-ASA linked to sulfapyridine
o5ASA is only released in Large Intestine via bacteria cleavage (N=N)
oThe non-therapeutic sulfapyridine causes most side effects (nausea, headaches)
oIf formulated with a pH coating, 5-ASA may be released through entire intestine

56
Q

Glucocorticoids:

A

oGeneral inflammatory inhibitor
1) Steroid-responsive: In these patients (~40%) symptoms improve over 1-2 weeks, and the disease remains in remission as the steroids are tapered off
2) Steroid-dependent: These patients (30-40%) respond to steroids as well, but experience relapse of the disease with tapering of the steroids
3) Steroid- unresponsive: As indicated, these patients (15-20%) do not respond to steroid treatment.

57
Q

Glucocorticoids use:

A

oUsed for acute treatment of moderate-to- severe
oNOT useful in maintaining remission oLOTS of side effects:
- Weight gain, moon-face, stress and emotional responses
- Steroid-dependent diabetes
- Increased risk of infection

58
Q

Immunosuppresants:

A

oDrugs usually developed for tissue rejection or cancer
oThiopurine derivatives: -DNA synthesis inhibitors (used in cancer work)
- Mercaptopurine and azothiopurine
- May take weeks to months (immune cell lifespan)

59
Q

Thiopurines:

A

oReserved for steroid-resistant or – dependent patients
oUseful in remission and reduction of relapse (UC and CD)
oNOT useful for acute attacks (long onset time)
oSmall risk of major infection, esp in cotreatment with steroids

60
Q

Methotrexate (MTX):

A

oDihydrofolate reductase inhibitor- blocks DNA synthesis
oAlso reserved for steroid-resistant or – dependent patients

61
Q

Cyclosporine:

A

oCalcineurin inhibitor (tissue transplantation)
oSerious side-effects (severe immune suppression)-only used for the MOST serious cases of UC and CD
oUsed right before surgery
o50-80% of severe UC patients respond to cyclosporin-levels must be CONSTANTLY monitored

62
Q

TNFa inhibitors:

A

oTNFa is a major pro-inflammatory ligand
oInhibition of this is used to treat other inflammatory diseases, such as eczema and rheumatoid arthritis
oInfliximab (Remicade) is an engineered antibody-It may kill the cell to which it attaches-Has very prolonged effects
oEtanercept also reduces TNFa but is NOT effective as a UC treatment
oThe prolonged effect may be due long
half-life of the drug (8-10 days)
oIf this drug kills the immune cells, then repopulation in the submucosa is required
oVERY expensive (very difficult to produce)
oIncreases chances of serious lung infection, especially tuberculosis (submucosal protection)

63
Q

Autoimmune diseases (AD), treatments and COVID19:

A

oThose with AD have shown enhanced severity, hospitalization and mortality as a result of COVID19 infection
oThese may be attributable to either having the disease and/or undergoing immunosuppressant therapy
oAs the pandemic rages, as a clinician treating a patient with AD, one must be cognizant about the risks of being on vs off treatment

64
Q

Thalidomide – an emerging Treatment Option for UC and CD:

A

oThalidomide babies” Mothers used this in the late 50’s and early 60’s for nausea-this caused severe birth defects (generally of the limbs)
oThalidomide-inhibitor of NF-kB, a transcription factor involved in inflammation
o“Though the most famous example of a “bad drug” it actually is very effective in immune
suppression and is being investigated for many other diseases

65
Q

Anti-and Pro-biotics:

A

oUC and CD may be due to changes in intestinal bacteria
oDrugs investigated that may change the proportions of different bacteria

66
Q

There are thought to be over 100 autoimmune disease:

A

oThese can affect almost any organ/tissue of the body
oNew ones are constantly being identified or existing diseases are being attributed to auto-immune diseases
oLupus, MS, Type 1 diabetes, Guillan Barre syndrome, Psoriasis, Grave’s disease, Vasculitis, etc…

Pharmacology (Winter) (23 decks)

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