Immunosuppressive Drugs Flashcards
Skeletal autoimmune diseases
Rheumatoid arthritis (RA)
Systemic autoimmune diseases
Systemic lupus erythematosus
Polyarteritis nodosa
Sarcoid
Neruonal autoimmune diseases
Multiple sclerosis
GI autoimmune diseases
Chron’s disease
Ulcertive colitis
Celiac disease
Pernicious anemia (lack of GIF)
Skin autoimmune diseases
Vitiligo
- Light patches due to death of melanocytes
Psoriasis
- Scaly painful and associated w/ joint disease
Secretory autoimmune diseases
Sjogrens
- Salivary and tear glands
Graves
- Hypothyroidism
Addison’s
- Adrenal cortex
Diabetes
Pathway to cytotoxic B cells vs antigen specific B cells
Cytotoxic B cells
Mac→CD4 T cell→IL-2→Cyt. B cells
Antigen specific B cells
Mac→CD4 T cell→IL-4,5→Ant. specific B cells
What activates Janus kinases?
What do janus kinases activate?
IL receptors (1, 6, 12, 23)
TNF receptor
Janus kinases→gene activation→IL-2 act.→New T cells/more gene activation
Role of calcium in CD4
Ca→Act. calcineurin→Act. NFAT→gene activation→IL-2 act.→New T cells/more gene activation
What are all of the receptors on CD4
TNF
IL-1
IL-6, 12, 23
CD2
Alpha integrins
IL-2
Concerns w/ all immunosuppressants
Infection
May cause malignancy
Atgam
ATGam
Tx: Acute renal transplant injection
Immunosuppressant
Antithymocyte globulin (ATG)–Polyclonal antibodies
Effects: Reduces circulating T cells(Wikipedia)
_A_ffects _T_ cell activation
SE:
- Polyclonal antibodies may lead to allergic rxn
- From horse or rabbit
Abatacept
Tx: RA
Immunosuppressant
Mech: binds to and inh. CD80, CD86 receptors
Affects T cell activation
ABatacept CD80+86 receptors
_A_batacept for _A_rthritis
Belatacept
Tx: Renal transplantation
Immunosuppressant
Mech: binds to CD80, CD86 receptor
Affects T cell activation
SE:
- Increase malignancy
ABatacept CD80+86 receptors (Belatacept too)
Abatacept: RA Belatacept: Kidney trans.
Monoclonal antibody naming
Ending: -mab
Middle of name=target:
- “li” or “i”-immune
- “tu”-tumor
Connecting letters=Source:
- xi=chimeric-mouse Ab w/ some human Ab substituted
- Most antigenic
- zu=humanized-human Ab w/ some mouse parts
- u=fully human
- Least antigenic
*Always given parenterally
Natalizumab
Nata-li-zu-mab
MAb affecting immune sys. from humanized source
Immunosuppressant
Tx: Chron’s + MS
Mech: Binds to alpha integrin binding site on CD4 (and other immune cells)
Not really a receptor but a “binding site”
SE:
- Linked w/ progressive multifocal leukoencephalothopy (PML)
- Fatal viral disease of CNS
_Nat_ty’s give you the beer shits
_Nat_alizumab=Chron’s
natALIzumab-binds ALpha Integrin binding site
Tocilizumab
Toci-li-zu-mab
MAb affecting immune sys. from humanized source
Immunosuppressant
Tx: RA
Mech: Binds to IL-6 receptor
- Football players get tackled so they have RA but all of the ladies want to have risque sex w/ them*
- Football players get tocilizumab so they have RA but all the ladies want to have IL-6 receptor with them*
Ustekinumab
Ustek-i-nu-mab
MAb affecting immune sys. from human source
Immunosuppressant
Tx: Psoriasis
Mech: Binds to IL-12, 23
- Michael Jordan used to wear #23 until someone stole his jersey and he had to wear #12 (true story). Whoever stole it ought to be sorry.*
- MJ uste-kinumab wear IL-23 then wore IL-12. They ought to be psoriases.*
What agents bind TNF
Etanercept (RA)
Infliximab (RA,C)
Certolizumab (RA,C)
Adalimumab (RA)
Golimumab (RA, etc)
Think TNF=TNT (dynamite)
Explosions In Caves Affect Gollum
Etanercept
Tx: RA
Immunosuppressant
Mech: Binds TNF
Route: SubQ (in comb. w/ other immunosupp)
Synthesized molecule
eTaNercept-binds TNF
Infliximab
Infli-xi-mab
Tx: RA, Chron’s
Immunosuppressant
Mech: Binds TNF
Route: IV
SE:
- Infusion→itching, hypertension, fever
- Concerned if pt has pre-existing infection like fungus or Tb b/c infection may become worse
- If you are _inflex_ible (from sitting on the toilet=Chron’s) take _inflix_imab although it may lead to _i_tching*
- May also lead to hyperTensioN and Fever–binds to TNF*
Adalimumab
Ada-li-mu-mab
Tx: RA
Immunosuppressant
Mech: Binds TNF
Certolizumab
Tx: RA, Chron’s
Immunosuppressant
Mech: Binds TNF
Golimumab
Tx: RA, Ulcerative colitis, psoriatic arthritis
Immunosuppressant
Mech: Binds TNF
Anakinra
Tx: RA
Mech: Blocks IL-1 receptor
Route: SubQ
Used w/ other immunosuppressants like methotrexate
Should NOT be used w/ TNF inh b/c may lead to serious infection (too much suppression)
anakinRA=RA=RAceptor blocker
Rilonacept
Tx: RA
Mech: Binds to IL-1
Route: SubQ
Used w/ other immunosuppressants like methotrexate
Should NOT be used w/ TNF inh b/c may lead to serious infection (too much suppression)
- Anakinra-blocks IL1 receptor*
- Rilonacept-binds to IL1*
Cyclosporine
Tx: Transplants, psoriasis, dry eye (tear duct inflam)
Fungus derived
Route: Emulsion
Mech:
Binds to intracellular protein-cyclophyllin
Complex forms and _inh. enzyme-_calcineurin phosphatase
Enzyme inhibitor
Prevents act. of NFAT complex which then prevents act of gene that codes for IL2,3 and TNF alpha
T cell inhibited
Kinetics
- Metabolized by P450
- Lots of drug interactions-esp. antibiotics
SE:
- Nephrotoxicity
- Hepatotoxicity
- Cosmetic changes
- Hypertrichosis
- Gingival hyperplasia
- Increased cholesterol (reversible)
- Mild hypertension (reversible)
Cyclosporin-binds to Cyclophyillin→inh. Calcinuerin, used for Crusty eyes and skin, may cause Cosmetic Changes, î Cholesterol, Cidney (kidney) damage
- What else affects calcinuerin phosphatase? Tacrolimus*
- Cyclosporine: Binds cyclophyllin*
- Tacrolimus: Binds FK protein*
Tacrolimus
Tx: Transplantation
Immune suppression
Mech:
- Binds to FK binding protein
- _Inh. calcineurin phosphatase _
- Like cyclosporin but binds to diff protein→inh. of cytokine synth
More eff. than cyclosporin A-Increase max inh. effect
SE:
- Nephrotoxicity
- Neurotoxicity
- Alopecia (baldness)
- Less cosmetic effects than cyclosporine
- Diabetes
Metab by P450
- Tacrolimus for transplantations*
- What else binds to FK protein? Sirolimus/Everolimus*
- Tacrolimus: Inh calcinuerin phosphatase*
- Sirolimus: Inh kinase*
- What else affects calcinuerin phosphatase? Cyclosporine*
- Cyclosporine: Binds cyclophyllin*
- Tacrolimus: Binds FK protein*
Glucocorticoids
Tx: Inh. all immune processes
Immunosuppressant
Mech:
- GC cross CM, bind to receptor and dimerize, then affect trans.
- Decrease PGE and leukotrienes
- Alter migration of immune cells
Often used in comb. w/ other immunosuppressants
SE: Sig SE w/ long term use. Refer to other lecture
Sirolimus
Tx: Transplant, psoriasis
Mech: Bind to FK binding protein
inh. kinase required for binding of IL-2 induced transcription factors to DNA→decreased cytokine production
Often used in combination w/ glucocorticoids
SE:
- Some renal toxicity
- Less than tacrolimus
- Synergistic effect w/ used in comb w/ many immunosupp.
- Some lung toxicity
Metab by P450
- What else binds to FK protein? Tacrolimus*
- Tacrolimus: Inh calcinuerin phosphatase*
- Sirolimus/Everolimus: Inh kinase*
Everolimus
Tx: Transplant, psoriasis
Mech: Bind to FK binding protein
inh. kinase required for binding of IL-2 induced transcription factors to DNA→decreased cytokine production
Often used in combination w/ glucocorticoids
SE:
- Some renal toxicity
- Less than tacrolimus
- Synergistic effect w/ used in comb w/ many immunosupp.
- Some lung toxicity
Metab by P450
…
- What else binds to FK protein? Tacrolimus*
- Tacrolimus: Inh calcinuerin phosphatase*
- Everolimus/Sirolimus: Inh kinase*
Basiliximab
Immunosuppressant
Mech: IL-2 receptor blocker
Used w/ CSA
65% human (chimeric)
Hypersensitivity rxn
- Hypotension
- Bronchospasm
- Pulmonary edema
Harry Potter is a hypersensitive bitch when he fights the basilisk in the Chamber of Secrets, which is the 2nd reading in the series
Hypotension + Pulmonary edema, hypersensitivity, bronchospasm, basiliximab, used w/ CSA. IL-_2_ receptor blocker
Which immunosuppressive MABs couldn’t you give for RA?
Natalizumab (Chron’s and MS)
Ustekinumab (Psoriasis)
Basiliximab
Tofacitinib
-ib=inhibitor (often kinase inh)
Mech: Janus kinase inh.
- Inh signal pathways of cytokines and ILs
- Modifies effect of cytokines on gene exp
- Prevents act. of signal transducers and activators of trans.
SE:
- Increase infection
- Increase malignancy
Azathioprine
Tx: RA, Chron’s, trans
Prodrug
Mech:
- Converted to 6-mercaptopurine
- Inh. synth of purines (guanosine required for DNA synth)
-
Inh. several enzymes responsible for GMP synth
- Non specific
SE:
- Bone marrow suppression→
- Megaloblastic anemia
- Thrombocytopenia
- Leukopenia
6-mercaptopurine is also an anti-cancer agent
Mycophenolate mofetil
Tx: Transplants and lupus
More specific replacement than azothioprine
Inh. enzyme inosine monophosphate DH→Inh. guanisine synth.
SE:
Bone marrow decrease
GI cell disruption
Methotrexate
Tx: DOC early tx of RA
Used more as immunosuppressant than anti-cancer drug
DMARD-Disease modifying anti-rheumatic drug
Actually stops progression of RA rather than just treat symptoms
Mech:
- Analog of Folic Acid
- Inh. enzyme: Dihydrofolate reductase
- PABA→Folic acid⇒Dihydrofolic acid⇒tetrahydrofolic acid
- ⇒ indicate where DHFR works
- Inh. mammalian cell division
- Inh. lots of folic acid dependent processes, especially in cells w/ rapid turnover (at high doses):
- GI
- Fetal development
- Blood cells
- Immune cells more susceptible than above though
- Inh. lots of folic acid dependent processes, especially in cells w/ rapid turnover (at high doses):
Leflunomide
Immunosuppressant
Prodrug. Gets converted into Teriflunomide
Mech: Inhibits dihydroorotate DH
- Rate limiting step in production of pyrimidine (so inh. pyr. production)
- Decrease in UMP and TMP
- More effect on lymphocytes
SE:
- Diarrhea and abdominal pain (rapidly replicating GI cells)
- Flu like symptoms w/ flunomides
- Teratogenic
- Must take bile acid binding agent to get rid of all of drug if pregnant
Inhibits P450
- You no ride w/ me–get another Designated Driver*
- “Flu-no-ride w/ me. Get another DD (inh. Dihydroorate DH)*
Teriflunomide
Immunosuppressant
Gets converted from prodrug Leflunomide
Mech: Inhibits dihydroorotate DH
- Rate limiting step in production of pyrimidine (so inh. pyr. production)
- Decrease in UMP and TMP
- More effect on lymphocytes
SE:
- Diarrhea and abdominal pain (rapidly replicating GI cells)
- Flu-like symptoms w/ flunomides
- Teratogenic
- Must take bile acid binding agent to get rid of all of drug if pregnant
Inhibits P450
- You no ride w/ me–get DD*
- “Flu-no-ride w/ me. Get DD (dihydroorate DH)*
Hydroxychloroquinone
Immunosuppressant
Mech:
- Taken up by macs and conc. in mac lysosomes
- Interferes w/ mac. processing of antigens (1st step in immune process)
Toxicities:
- GI fxn
- Dermatitis
-
Irr. retinal damage
- Retinal changes and visual disturbances may progress even after discontinuation
