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Genetics; Protection II > Immunosuppressive Drugs > Flashcards

Immunosuppressive Drugs Flashcards

1
Q
  • Primitive, does not require priming
  • Most active early in an immune response
  • Major effectors: Complement
    1. Granulocytes
    2. Monocytes/macrophage
    3. NK cells
    4. Mast cells, basophils
A

Innate-natural

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2
Q
  • Antigen-specific, depends on Antigen exposure or priming
  • Progressively dominant over time
  • Major effectors:
    1. B lymphocytes -> Antibody
    2. T lymphocytes -> helper, cytolytic and regulatory (suppressor cells)
  • Important in the normal immune response to infection and tumors
  • Also mediate transplant rejection and autoimmunity
  • Modulation of immune response: immunosuppression
    • Tolerance
    • Immunostimulation
A

Adaptive-learned

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3
Q

4 Major Classes of Immunosuppressives

A
  • Glucocorticoids
  • Calcineurin inhibitors
  • Antiproliferative and antimetabolic agents
  • Antibodies
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4
Q

“Holy Grail” of Immunomodulation

A

Induction and maintenance of immune tolerance –> active state of Ag-specific non-responsiveness (the body will not reject organs transplanted to the body)

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5
Q
  • Dampen the immune response in organ transplantation and autoimmune disease (the body attacks its own system)
  • Tx requires lifelong use
  • Non-specifically suppress the entire immune system —> patients exposed to higher risks of infection and cancer
A

Immunosuppression

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6
Q

General approach to Organ Transplantation Tx

5 general principles:

A
  1. Carefully prepare the patient and select the best available ABO blood type–compatible HLA match for organ donation
    o Sometimes not followed because of lack of donors. The patients are just bombarded with immunosuppressives and have a higher risk of organ rejection.
  2. Employ multitier immunosuppressive therapy; simultaneously use several agents, each of which is directed at a different molecular target within the allograft response. Synergistic effects permit the use of various agents at relatively low doses, thereby limiting specific toxicities while maximizing the immunosuppressive effect
    > immunosuppression required to gain early engraftment/Tx established rejection than to maintain long term immunosuppression
  3. Employ intensive induction and lower-dose maintenance drug protocols; greater immunosuppression is required to gain early engraftment or to treat established rejection than to maintain long-term immunosuppression. The early high risk of acute rejection is replaced over time by the increased risk of the medications’ side effects, necessitating a slow reduction of maintenance immunosuppressive drugs.
  4. Careful investigation of each episode of transplant dysfunction is required, including evaluation for recurrence of the disease, rejection, drug toxicity, and infection (keeping in mind that these various problems can and often do coexist).
  5. Reduce dosage or withdraw a drug if its toxicity exceeds its benefit. Ideal before transplantation to have HLA typing
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7
Q

Used to delay the use of calcineurin inhibitors or to intensify initial immunosuppressive Tx in patients at high risk of rejection

A

Biological Induction Therapy

  1. Repeat transplants
  2. Broadly presensitized patients
  3. African-Americans
  4. Pediatric patients
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8
Q
  1. Repeat transplants
  2. Broadly presensitized patients
  3. African-Americans
  4. Pediatric patients
A

Biological Induction Therapy

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9
Q
  1. Repeat transplants
  2. Broadly presensitized patients
  3. African-Americans
  4. Pediatric patients
A

Biological Induction Therapy

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10
Q

Biological Induction Therapy has 2 groups:

A
  1. Depleting agents
  2. Immune modulators
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11
Q

MOA: Deplete the recipient’s CD3+ cells at the time of transplantation and Ag presentation

A

Depleting agents

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12
Q

a. Lymphocyte immune globulin
b. ATG (Antithymocyte globulin) – most commonly used
c. Muromonab –CD3 mAb
d. Deplete the recipient’s CD3+ cells at the time of transplantation and Ag presentation

A

Depleting agents

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13
Q

MOA: Block IL-2-mediated T-cell activation by binding to α chain of IL-2R (CD25)

A

Immune modulators

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14
Q

Anti-IL-2RmAbs

Block IL-2-mediated T-cell activation by binding to α chain of IL-2R

A

Immune modulators

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15
Q
  • Multiple drugs used simultaneously
  • Calcineurin inhibitor, glucocorticoids, mycophenolate (purine metabolism inhibitor) – each directed at a discrete step in T-cell activation
A

Maintenance Immunotherapy

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16
Q
  • Agents directed against activated T cells
  • Glucocorticoids in high doses (pulse therapy)
  • Polyclonal antilymphocyte Ab
  • Muromonab-CD3
A

Therapy for Established Rejection

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17
Q

What is the main glucocorticoid?

A

Cortisol (hydrocortisone)

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18
Q
  • Alterations in carbohydrate, protein, and lipid metabolism
  • Maintenance of fluid and electrolyte balance
  • Preservation of normal fxn of:
    o CVS
    o Kidney
    o Skeletal Muscle
    o Endocrine
    o Nervous
  • Gives organisms the capacity to resist stressful circumstances
    o pts. with hypercortisolism - more prone to infection
A

PHYSIOLOGIC FUNCTIONS

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19
Q

Immunosuppressive actions

A
  • 1 of Major pharmacologic uses
  • Immune mediators associated w/ inflammatory response
  • dec vascular tone –> lead to CVS collapse if unopposed by adrenal corticosteroids CHO andrenal corticosteroids
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20
Q

Stimulate liver to form glucose from amino acids and glycerol and store glucose as liver glycogen

A

CHO and CHON Metabolism

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21
Q

o Diminish glucose utilization
o Increase CHON breakdown and synthesis of glutamine
o Activate lipolysis
o Provide amino acids and glycerol for gluconeogenesis
o Increase blood glucose levels
*Steroids can cause hyperglycemia

A

CHO and CHON metabolism: Periphery

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22
Q

Redistribution of body fat in setting of endogenous or
pharmacologically induced hypercortism
o Buffalo hump
o Moon facies
o Supraclavicular a rea
o Loss of fat in extremities
- Increase in FFA after glucocorticoid administration

A

Lipid Metabolism

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23
Q

Aldosterone

A

Electrolyte and Water Balance

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24
Q
  • Mineralocorticoid – induced changes in renal Na+

- Enhance vascular reactivity to other vasoactive substances

A

CVS

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25
Q

Excessive amounts-impair muscle fxn (skeletal muscle wasting)
o Steroid myopathy

A

Skeletal Muscle

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26
Q

Indirect effects
o Maintenance of BP, plasma glucose conc., electrolyte conc.
o Effects on mood, behavior and brain excitability

A

CNS

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27
Q
  • Profoundly alter the immune response of lymphocytes
  • MOA: lyse and induce the redistribution of lymphocytes
  • Rapid, transient decrease in peripheral blood lymphocyte counts
  • Little effect on humoral immunity

Absorption, Transport, Metabolism, and Excretion
Orally effective
After absorption , >=90% in plasma is reversibly bound to protein

A

Anti-inflammatory and Immunosuppressive actions

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28
Q

Absorbed systemically from sites of local administration

A

o Synovial spaces – injection
o Conjunctival sac – eye drops
o Skin -creams and ointments for inflammatory reactions
o Respiratory tract – as inhalers

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29
Q

Bound to 2 plasma proteins

A

o Corticosteroid-binding globulin (CBG)/transcortin

o Albumin

30
Q
  • Result from withdrawal – esp. abrupt withdrawal
  • Result from continued use at supraphysiological doses
A

TOXICITY

31
Q

Withdrawal Treatment

A
  • Acute adrenal insufficiency – most severe
    o Adrenal collapse due to overly rapid withdrawal of steroids after prolonged Tx has suppressed the HPA (hypothalamic pituitary-adrenal axis)
    o Withdraw steroids slowly

Overly rapid w/drawal of steroids after prolonged Tx has suppressed the HPA axis

32
Q

Continued use

A
  • Fluid and electrolyte abnormalities – Na and K
  • Hypertension
  • Hyperglycemia
  • Increase susceptibility to infection
  • Osteoporosis
  • Myopathy
  • Behavioral disturbances – nervousness, insomnia, changes in mood or psyche, overt psychosis
    *cause roid rage in men – aggressive behavior
  • Cataracts
  • Growth arrest – in children
  • Characteristic habitus of steroid overdose
    o Fat redistribution
    o Striae
    o Ecchymoses - purplish lesions all over the body
33
Q

THERAPEUTIC USES

Principles

A
  • Single dose of glucocorticoid, even a large one –> without harmful effects
  • Short course Tx (up to 1 week) –> unlikely to be harmful - > 1 week –> time - and dose-related increases in the incidence of disabling and potentially lethal effects
  • Abrupt cessation after prolonged Tx –> adrenal insufficiency (may be fatal)

IMPT!!!
If to be given over long periodstrial and error dose
- Lowest to achieve desired effect

34
Q

THERAPEUTIC USES

Principles

A
  • Single dose of glucocorticoid, even a large one –> without harmful
    effects
  • Short course Tx (up to 1 week) –> unlikely to be harmful
  • > 1 week –> time - and dose-related increases in the incidence of disabling and potentially lethal effects
  • Abrupt cessation after prolonged Tx –> adrenal insufficiency (may be
    fatal)
35
Q

If to be given over long periods –> trial and error dose

A

Lowest dose to achieve desired effect

36
Q

If goal is relief of pain/distressing symptoms

A

o Steroid dose gradually reduced until worsening symptoms indicate that minimal acceptable dose has been found

o Substitute w/ NSAIDS-facilitate tapering glucocorticoid dose

37
Q

If goal is relief of pain/distressing symptoms

A

o Steroid dose gradually reduced until worsening symptoms indicate that minimal acceptable dose has been found

o Substitute w/ NSAIDS-facilitate tapering glucocorticoid dose

38
Q

Life-threatening disease

A

o Large initial dose aimed at rapid control of crisis
o If no benefit –> double/triple dose
o After initial control –> dose reduction under careful supervision
- In COVId 19 cases, glucocorticoids are given only to severe cases

39
Q

Uses:
- Transplant rejection
- GVHD in BM transplantation
- Autoimmune Disorders
- Limit allergic reactions that occur with other immunosuppressives
- Block 1st dose cytokine storm caused by Tx w/ Muromonab-CD3 and ATG

A
  • Transplant rejection
    o High-dose pulses of IV methylprednisolone Na succinate
    (SOLU-MEDROL)
    o Reverse acute transplant rejection
    o For acute exacerbations of selected autoimmune disorders
  • GVHD in BM transplantation
  • Autoimmune Disorders
    o RA (Rheumatoid Arthritis)
    o SLE (Systemic Lupus Erythematosus)
    o Systemic dermatomyositis
    o Psoriasis
  • Limit allergic reactions that occur with other immunosuppressives
  • Block 1st dose cytokine storm caused by Tx w/ Muromonab-CD3 and ATG
40
Q

Most effective immunosuppressive drugs in routine use

A

CALCINEURIN INHIBITORS

  • Cyclosporine
  • Tacrolimus
41
Q
  • MOA: Target intracellular signaling pathways induced as a
    consequence of T-cell receptor activation
  • Bind to an immunophilin (cyclophilin for Cyclosporine) (FKBP-12 for
    Tacrolimus) –> resulting in subsequent interaction with Calcineurin
    to block its phosphatase activity
A

CALCINEURIN INHIBITORS

42
Q
  • An antibiotic
  • Macrolide produced by Streptomyces tsukubaensis
  • Slightly greater efficacy and ease of blood level monitoringn = preferred in most transplant centers
  • MOA: inhibits T-cell activation by inhibiting Calcineurin
  • Oral administration as capsules, also as a solution for injection
  • Target concentrations
    o Early preoperative period = 10-15 ng/ml
    o 3 months after transplantation = 100-200 ng/ml
  • Food decreases rate and extent of absorption – given 15-30 minutes before or after meals
  • T ½ -12 hours
  • Excreted mainly in feces
A

TACROLIMUS

43
Q

Therapeutic uses of Tacrolimus

A
  • Prophylaxis of solid-organ allograft rejection
  • Rescue Tx in patients w/ rejection episodes despite Tx levels of Cyclosporine
  • Initial oral doses: 0.2 mg/kg/day for adult kidney transplant patients
    o 0.1-0.15 mg/kg/day for adult liver transplant patients
    o 0.15-0.2 mg/kg/day for pediatric liver transplant
44
Q

Tacrolimus toxicity

A
  • Nephrotoxicity
  • Neurotoxicity (tremor, headache, motor disturbances, seizures)
  • GI complaints
  • Hypertension
  • Hyperkalemia
  • Hyperglycemia
  • Diabetes
45
Q

Drug Interactions with Tacrolimus

A
  • Blood levels and renal function monitored closely
  • Co-administration w/ Cyclosporine-additive/synergistic
    nephrotoxicity
  • Delay of at least 24 H before switching a patient from Cyclosporine to
    Tacrolimus
46
Q
  • Lipophilic and highly hydrophobic-formulated using castor oil to
    ensure solubilization
  • produced by the fungus Beauveria nivea
  • MOA: suppresses some humoral immunity, greater effective
    against T cell – dependent immune mechanisms
    o Preferentially inhibits Ag-triggered signal transduction in T
    lymphocytes, including IL-2
    o Administered IV or p.o.
    o Administration with food delays and decreases absorption
    o Extensively metabolized in the liver
A

CYCLOSPORINE

47
Q

Therapeutic uses: CYCLOSPORINE

A
  • Kidney, liver, heart and other organ transplantation
  • RA
  • Psoriasis
  • Dose varies, depending on organ transplanted
  • Initial dose generally not given before transplant because of
    concerns of nephrotoxicity
48
Q

Toxicity: CYCLOSPORINE

A
  • Renal dysfunction and hypertension – main
  • Hirsutism
  • Tremor
  • Hyperlipidemia
  • Gum hyperplasia
  • Nephrotoxicity: major reason for cessation/modification of Tx
49
Q

Drug Interactions: CYCLOSPORINE

A 
- Drugs that inhibit CYP3A – decrease metabolism of cyclosporine and
enhance toxicity
o Ca ++ channel blockers
o Antifungal agents
o Antibiotics (Erythromycin)
o Grapefruit juice
- Drugs that induce CYP3A – cause increase excretion of cyclosporine
o Antibiotics (Nafcillin, Rifampin)
o Anticonvulsants
50
Q

Anti-Proliferative and Antimetabolic drugs

A
  • SIROLIMUS
  • EVEROLIMUS
  • AZATHIOPRINE
  • MYCOPHENOLATE MOFETIL
51
Q
  • Inhibits T-lymphocyte activation and proliferation downstream of the
    IL-2 and other T-cell growth factor receptors
  • Immunophilin: FKBP-12
  • Binds to and inhibits a protein kinase – mTOR
  • Absorbed rapidly after oral administration
  • Should be taken w/ or w/o food
  • Blood levels monitored closely
  • T ½ after multiple doses=62 hours

Therapeutic uses
- Prophylaxis of organ transplant rejection in combination w/ a
decrease dose of calcineurin inhibitor and glucocorticoids
- Daily maintenance dose decrease by 1/3 in patients w/ hepatic
impairment
- Incorporated into stents to inhibit local cell proliferation and blood
vessel occlusion

Toxicity
- Dose-dependent increase in serum cholesterol and triglycerides
- Anemia, leukopenia, thrombocytopenia, mouth ulcer, hypokalemia,
proteinuria, GI effects
- Delayed wound healing

A

SIROLIMUS

52
Q
  • Shorter t ½
  • Shorter time to achieve steady-state concentrations
  • Combination with calcineurin inhibitor produces worse renal
    function at 1 year
A

EVEROLIMUS

53
Q
  • Purine antimetabolite
  • Inhibition of cell proliferation
  • Well absorbed orally, max blood levels w/in 1-2 hours after
    administration
  • T ½ = 10 min

Therapeutic uses

  • Adjunct for the prevention of organ transplant rejection
  • Severe RA
  • Usual starting dose – 3-5 mg/kg/day
Toxicity
- BM suppression
- Leukopenia (common)
- Thrombocytopenia
- Anemia
- Increase susceptibility to infections (esp. Varicella, Herpes simplex
virus)
- Hepatotoxicity
- Alopecia
- GI toxicity
- Pancreatitis
- Increase risk of neoplasia
A

AZATHIOPRINE

54
Q
  • Active drug: MPA-mycophenolic acid
  • Selective, noncompetitive, reversible inhibitor of inosine
    monophosphate dehydrogenase (IMPDH)
  • Inhibits lymphocyte proliferation and function- no antibody
    formation, cellular adhesion, migration

Therapeutic uses
- Prophylaxis of transplant rejection
- Combined with glucocorticoids and a calcineurin inhibitor but not
Azathioprine
- Renal transplant patients-1 g p.o. or IV BID

Toxicity
- GI and hematologic
o Leukopenia
o Pure red cell aplasia
o Diarrhea
o Vomiting
o Increase evidence of some infections (sepsis associated with
CMV)
o Pregnancy: congenital anomalies, increase risk of pregnancy
loss
A

MYCOPHENOLATE MOFETIL

55
Q

GVHD, RA, psoriasis, some cancers

A

Methotrexate

56
Q

Childhood nephrotic syndrome
Severe SLE

A

Cyclophosphamide

57
Q

given to pregnant women since it causes congenital

abnormalities; produces phocomelia- baby will have no limbs

A

Thalidomide

58
Q
  • Polyclonal and monoclonal Ab against lymphocyte cell-surface Ag
  • For prevention and treatment of organ transplant rejection
  • Generated by repeated injections of human thymocytes (ATG) or
    lymphocytes (ALG) into horses, rabbits, sheep or goats –> purify
    serum Ig fraction
A

BIOLOGICAL IMMUNOSUPPRESSION Ab AND FUSION RECEPTOR PROTEIN

59
Q
  • Purified gamma globulin from serum of rabbits immunized with
    human thymocytes
  • Contains cytotoxic Ab that bind to CD2,CD3, CD4, CD8, CD11a,
    CD18, CD25, CD44, CD45, HLA class I and II molecules on the Tlymphocyte
    surface
  • Ab deplete circulating lymphocytes by Direct cytotoxicity
    o Block lymphocyte function by binding to cell surface molecules
    Therapeutic uses
  • Induction immunosuppression
  • Only approved indication: Tx of acute renal transplant rejection in
    combination with other immunosuppressives
  • Given to renal transplant patients w/ delayed graft function to avoid
    early Tx w/ calcineurin inhibitorsà aid in recovery from ischemic
    reperfusion injury
    Toxicity
  • Fever and chills
  • Potential for hypotension
  • Premedication w/ corticosteroids, acetaminophen, antihistamine
A

ANTITHYMOCYTE GLOBULIN (ATG)

60
Q
  • Anti-CD3 Monoclonal Ab
    o Muromonab-CD3:induces rapid internalization of the T-cell
    receptoràprevents subsequent Ag recognition
    o After administration
    • Depletion and extravasation of a majority of T cells from
    the bloodstream, LN and spleen
    • Reduces function of remaining T cells
    Therapeutic uses
  • Tx of acute organ transplant rejection
    o Circulating T cells disappear from blood within min and return
    within 1 week after termination of Tx
    Toxicity
  • Major side effect: “cytokine release syndrome”
    o 30 min after infusion, lasts for hours
    o Increased serum levels of cytokines
    o Symptom worse with 1st dose
    o High fever, chills/rigor, headache
    o Tremor, N & V, diarrhea
    o Abdominal pain, malaise, myalgias
    o Generalized weakness
    Prevention
  • Administer glucocorticoids before injectionà prevents release of
    cytokines
A

MONOCLONAL ANTIBODIES

61
Q
  • Dacluzimab
  • Basiliximab
  • MOA: binding of the anti-CD25 mAbs to the IL-2 receptor on
    activated but not resting T cells

Therapeutic uses
- Prophylaxis of acute organ rejection in adults

Toxicity
- Anaphylactic reactions

A

ANTI IL-2 RECEPTOR (ANTI-CD25) ANTIBODIES

62
Q
  • mAb used in CLL (Chronic Lymphocytic Leukemia)
  • Targets CD52-present on lymphocytes, monocytes, macrophages, NK
    cellsàextensive lympholysis by inducing apoptosis of targeted cells
  • Renal transplantation-produces prolonged T and B cell depletion –
    allows drug minimization
A

ALEMTUZUMAB

- mAb used

63
Q

ANTI-TNF REAGENTS

A

Infliximab
Etanercept

64
Q
  • Binds to TNF-α-prevents binding to receptors
  • For moderate to severe Crohn’s disease
  • Ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, ulcerative
    colitis
A

Infliximab

65
Q
  • rheumatoid arthritis in unresponsive patients
  • Adalimumab
  • Toxicity: risk for serious infections
A

Etanercept

66
Q

IL-1 INHIBITION

A

Anakinra –human IL-1RA
Canakinumab – IL 1ϐ

67
Q
  • For Tx of joint dse in RA
  • Used alone or in combination with anti TNF agents
A

Anakinra –human IL-1RA

68
Q

For Cryoprin-associated periodic syndromes(CAPS)

A

Canakinumab – IL 1ϐ

69
Q

For Cryoprin-associated periodic syndromes(CAPS)

A

Canakinumab – IL 1ϐ

70
Q

LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 (LFA-1) INHIBITION

A

Efalizumab
Alefacept

71
Q
  • Humanized IgG1 mAb targeting the CD1 1a chain of lymphocyte
    function-associated antigen-1
  • Block T-cell adhesion, trafficking and activation
A

Efalizumab

72
Q
  • Human LFA-3-IgG1 fusion protein
  • Blocks interaction between LFA-3 and CD2
  • Interferes w/ T-cell activation
  • Approved for psoriasis
A

Alefacept

Genetics; Protection II (11 decks)

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