Immunosuppressive Drugs Flashcards
- 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
Innate-natural
- 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
Adaptive-learned
4 Major Classes of Immunosuppressives
- Glucocorticoids
- Calcineurin inhibitors
- Antiproliferative and antimetabolic agents
- Antibodies
“Holy Grail” of Immunomodulation
Induction and maintenance of immune tolerance –> active state of Ag-specific non-responsiveness (the body will not reject organs transplanted to the body)
- 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
Immunosuppression
General approach to Organ Transplantation Tx
5 general principles:
- 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. - 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 - 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.
- 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).
- Reduce dosage or withdraw a drug if its toxicity exceeds its benefit. Ideal before transplantation to have HLA typing
Used to delay the use of calcineurin inhibitors or to intensify initial immunosuppressive Tx in patients at high risk of rejection
Biological Induction Therapy
- Repeat transplants
- Broadly presensitized patients
- African-Americans
- Pediatric patients
- Repeat transplants
- Broadly presensitized patients
- African-Americans
- Pediatric patients
Biological Induction Therapy
- Repeat transplants
- Broadly presensitized patients
- African-Americans
- Pediatric patients
Biological Induction Therapy
Biological Induction Therapy has 2 groups:
- Depleting agents
- Immune modulators
MOA: Deplete the recipient’s CD3+ cells at the time of transplantation and Ag presentation
Depleting agents
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
Depleting agents
MOA: Block IL-2-mediated T-cell activation by binding to α chain of IL-2R (CD25)
Immune modulators
Anti-IL-2RmAbs
Block IL-2-mediated T-cell activation by binding to α chain of IL-2R
Immune modulators
- Multiple drugs used simultaneously
- Calcineurin inhibitor, glucocorticoids, mycophenolate (purine metabolism inhibitor) – each directed at a discrete step in T-cell activation
Maintenance Immunotherapy
- Agents directed against activated T cells
- Glucocorticoids in high doses (pulse therapy)
- Polyclonal antilymphocyte Ab
- Muromonab-CD3
Therapy for Established Rejection
What is the main glucocorticoid?
Cortisol (hydrocortisone)
- 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
PHYSIOLOGIC FUNCTIONS
Immunosuppressive actions
- 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
Stimulate liver to form glucose from amino acids and glycerol and store glucose as liver glycogen
CHO and CHON Metabolism
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
CHO and CHON metabolism: Periphery
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
Lipid Metabolism
Aldosterone
Electrolyte and Water Balance
- Mineralocorticoid – induced changes in renal Na+
- Enhance vascular reactivity to other vasoactive substances
CVS
Excessive amounts-impair muscle fxn (skeletal muscle wasting)
o Steroid myopathy
Skeletal Muscle
Indirect effects
o Maintenance of BP, plasma glucose conc., electrolyte conc.
o Effects on mood, behavior and brain excitability
CNS
- 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
Anti-inflammatory and Immunosuppressive actions
Absorbed systemically from sites of local administration
o Synovial spaces – injection
o Conjunctival sac – eye drops
o Skin -creams and ointments for inflammatory reactions
o Respiratory tract – as inhalers
Bound to 2 plasma proteins
o Corticosteroid-binding globulin (CBG)/transcortin
o Albumin
- Result from withdrawal – esp. abrupt withdrawal
- Result from continued use at supraphysiological doses
TOXICITY
Withdrawal Treatment
- 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
Continued use
- 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
THERAPEUTIC USES
Principles
- 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 periodstrial and error dose
- Lowest to achieve desired effect
THERAPEUTIC USES
Principles
- 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)
If to be given over long periods –> trial and error dose
Lowest dose to achieve desired effect
If goal is relief of pain/distressing symptoms
o Steroid dose gradually reduced until worsening symptoms indicate that minimal acceptable dose has been found
o Substitute w/ NSAIDS-facilitate tapering glucocorticoid dose
If goal is relief of pain/distressing symptoms
o Steroid dose gradually reduced until worsening symptoms indicate that minimal acceptable dose has been found
o Substitute w/ NSAIDS-facilitate tapering glucocorticoid dose
Life-threatening disease
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
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
- 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
Most effective immunosuppressive drugs in routine use
CALCINEURIN INHIBITORS
- Cyclosporine
- Tacrolimus
- 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
CALCINEURIN INHIBITORS
- 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
TACROLIMUS
Therapeutic uses of Tacrolimus
- 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
Tacrolimus toxicity
- Nephrotoxicity
- Neurotoxicity (tremor, headache, motor disturbances, seizures)
- GI complaints
- Hypertension
- Hyperkalemia
- Hyperglycemia
- Diabetes
Drug Interactions with Tacrolimus
- 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
- 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
CYCLOSPORINE
Therapeutic uses: CYCLOSPORINE
- 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
Toxicity: CYCLOSPORINE
- Renal dysfunction and hypertension – main
- Hirsutism
- Tremor
- Hyperlipidemia
- Gum hyperplasia
- Nephrotoxicity: major reason for cessation/modification of Tx
Drug Interactions: CYCLOSPORINE
- 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
Anti-Proliferative and Antimetabolic drugs
- SIROLIMUS
- EVEROLIMUS
- AZATHIOPRINE
- MYCOPHENOLATE MOFETIL
- 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
SIROLIMUS
- Shorter t ½
- Shorter time to achieve steady-state concentrations
- Combination with calcineurin inhibitor produces worse renal
function at 1 year
EVEROLIMUS
- 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
AZATHIOPRINE
- 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
MYCOPHENOLATE MOFETIL
GVHD, RA, psoriasis, some cancers
Methotrexate
Childhood nephrotic syndrome
Severe SLE
Cyclophosphamide
given to pregnant women since it causes congenital
abnormalities; produces phocomelia- baby will have no limbs
Thalidomide
- 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
BIOLOGICAL IMMUNOSUPPRESSION Ab AND FUSION RECEPTOR PROTEIN
- 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
ANTITHYMOCYTE GLOBULIN (ATG)
- 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
MONOCLONAL ANTIBODIES
- 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
ANTI IL-2 RECEPTOR (ANTI-CD25) ANTIBODIES
- 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
ALEMTUZUMAB
- mAb used
ANTI-TNF REAGENTS
Infliximab
Etanercept
- Binds to TNF-α-prevents binding to receptors
- For moderate to severe Crohn’s disease
- Ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, ulcerative
colitis
Infliximab
- rheumatoid arthritis in unresponsive patients
- Adalimumab
- Toxicity: risk for serious infections
Etanercept
IL-1 INHIBITION
Anakinra –human IL-1RA
Canakinumab – IL 1ϐ
- For Tx of joint dse in RA
- Used alone or in combination with anti TNF agents
Anakinra –human IL-1RA
For Cryoprin-associated periodic syndromes(CAPS)
Canakinumab – IL 1ϐ
For Cryoprin-associated periodic syndromes(CAPS)
Canakinumab – IL 1ϐ
LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 (LFA-1) INHIBITION
Efalizumab
Alefacept
- Humanized IgG1 mAb targeting the CD1 1a chain of lymphocyte
function-associated antigen-1 - Block T-cell adhesion, trafficking and activation
Efalizumab
- Human LFA-3-IgG1 fusion protein
- Blocks interaction between LFA-3 and CD2
- Interferes w/ T-cell activation
- Approved for psoriasis
Alefacept
