-
Glucocorticoids
- ↑ IκB expression, ↓ NFκB in immune cells = ↑ apoptosis of activated immune cells
- ↓ synthesis and release of proinflammatory cytokines (TNF-α, IL-1, IL-6,)
- Neutrophils and monocytes show ↓ chemotaxis, ↓ enzyme release
- ↓ T-cell production of IL-2 = ↓ T-cell proliferation
- Activation of CTLs inhibited
-
Antithymocyte globulin (ATG) & Antilymphocyte globulin (ALG)
- Animal immunized with T-cells
- Serum transfer containing anti-MHCs and anti-CDs
- Bind circulating lymphocytes cause cytotoxicity
-
Muromonab-CD3 (OKT-3)
- Kidney Transplantation
- Monoclonal Ab against CD3
- Causes internalization of TCR, ↑ apoptosis
- T-cell death due to complement activation
- Margination and redistribution to nonlymphoid organs
- T-cells disappear from circulation in mins, returning ~1 wk after cessation of OKT-3
-
Daclizumab & Basiliximab
- (Anti-CD25, Anti-IL-2R)
- Abs to the α-subunit of IL-2 receptor of activated T-cells
- Blocks IL-2 stimulation and increases apoptosis of activated T-cells
- Low toxicity; without cytokine release, anaphylaxis still possible
- Used in prophylactic combination (e.g., with CsA, glucocorticoids) to prevent acute renal rejection
-
Cyclosporine (Cyclosporin A, CsA)
- CsA enters cell and binds to cyclophilin (CyP)
- CsA-CyP complex binds to calcineurin (PP2B), inhibiting its ability to dephosphorylate NF-ATc
- NF-ATc is prevented from entering the nucleus, the transcriptional cascade required for T-cell activation doesn't occur
- CsA inhibits signal transduction, and blocks transcription of genes, including IL-2, required for T-cell activation & clonal expansion
- Metabolized by CYP3A4 (P-450) = drug interaction
-
Tacrolimus (FK506)
- Tacrolimus (FK506) enters the cell and binds to FKBP12 (FK binding protein 12)
- FK506-FKBP12 complex binds to and inhibits the phosphatase activity of calcineurin (PP2B)
- Inhibits signal transduction, and blocks transcription of genes, including IL-2, required for T-cell activation & clonal expansion
- Metabolized by CYP3A4 (P-450) = drug interaction
-
Sirolimus (Rapamycin)
- Kidney Transplantation
- Sirolimus binds to FKBP12 and the complex binds mTOR
- Inhibition of CdK2, arresting cells at the G1→ S transition
- Metabolized by CYP3A4 (P-450) = drug interaction
-
Mycophenolate mofetil
- Prodrug: hydrolyzed by mycophenolic acid (MPA)
- MPA is a reversible inhibitor of inosine monophosphate dehydrogenase, in the de novo pathway of purine (GMP) synthesis
- B and T lymphocytes are highly dependent upon de novo purine synthesis and are selectively inhibited
-
Azathioprine
- Kidney Transplantation
- Prodrug cleaved to 6-mercaptopurine (6-MP), which inhibits de novo purine synthesis 6-MP is phosphorylated via the salvage pathway and incorporated into DNA disrupting replication, transcription, function
- Metabolized by oxidation (xanthine oxidase) or methylation (thiopurine methyltransferase) in the liver before urinary elimination
-
Infliximab & Adalimumab
- Monoclonal Abs
- TNF-α inhibitors
- Decrease IL-1 and IL-6
-
Entanercept
- Human TNF-α receptor-IgG fusion protein
- Neutralizes TNF-α in the blood and tissues.
-
Antibody Drugs
- ATG
- ALG
- Muromonab-CD3 (OKT-3)
- Daclizumab & Basiliximab
- Infliximab & Adalimumab
-
TNF-α Inhibitors
- Infliximab & Adalimumab
- Etanercept
-
Calcineurin Inhibitors
- Cyclosporine (CsA)
- Tacrolimus (Fk506)
-
Antimetabolites
- Mycophenolate mofetil
- Azathiopine
-
Glucocorticoid Toxicities
- Supression of pituitary:adrenal axis leads to increased infection and malignancy
- Growth retardation and poor would healing
- Hypertension
- Osteopenia
-
ATG & ALG Toxicities
- Serum Sickness
- Anti-animal antibodies
-
Muromonab-CD3 (OKT-3) Toxicities
- Cytokine release syndrome
- Hypersensitivity reaction
-
Daclizumab Toxicities
Low toxiciity
-
Cyclosporine Toxicities
- Nephrotoxicity
- Gum hyperplasia
- Predisposes patients to viral infection
-
Tacrolimus Toxicities
- Nephrotoxicity
- Peripheral neuropathy
- Hypertension
- Plueral Effusion
- Hyperglycemia (combination with glucocorticoids can lead to diabetes)
-
Sirolimus (Rapamycin) Toxicities
- Hyperlipidemia
- Myelosupression (thrombocytopenia)
- Leukopenia
- Delayed wound healing
-
Mycophenolate Toxicities
- Leukopenia
- Diarrhea
- Vomiting
-
Azathioprine Toxicities
- Bone marrow supression
- Hepatotoxicity
- Toxic effects increased with allopurinol
-
Chlorpheniramine & diphenhydramine (Benadryl)
- 1st generation antihistamines
- Vasoconstricts
- Decrease vascular permeability
- Short duration
- Anti-nausea / anti-motion sickness
- Causes Sedation
-
Loratadine, fexofenadine, citrizine (Claratin, etc.)
- 2nd and 3rd generation antihistamines
- long duration
- not anti-nausea
- causes less sedation
-
Sumatriptan
- Serotinin agonist
- Vasoconstrictor
- Used for migrane headaches
-
Misoprostol
- PG16 analog
- Oral treatment for gastric ulcers
-
Glucocorticoids
- end in "one"
- inhibit arachadonic acid pathway
-
Zileuton
- Inhibits 5-lipoxygenase in leukotriene pathway
- Used for asthma
-
Zafirlukast
- Leukotriene receptor agonist
- Used for asthma
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