Immuno Drugs

H1 antihistamine and glucocorticoids

2nd generation of H1 inhibitors - drugs of choice

Prevent mast cell degranulation and inhibit the release of histamine

• low sedation

• minimal CNS effects → better than 1st gen

Many (not all) have the suffix -adine

A specific 2nd gen H1 inhibitor

• Smooth muscle relaxation (resp sys and vascular muscles)

• Decrease capillary permeability

• decreases flares and itch

• Stabilizes mast cells → Antiinflammation

• Safe for pregnancy

Treats things like angioedema, pruritis, etc

Grapefruit decreases absorption and bioavailability!

Activates and desensitizes TRPV1 → used in the treatment of pruritis

• beware, greater than 10 days use depletes substance P stores

Used for seasonal allergies and asthma control

• Reduces bronchial reactivity, mucosal edema, and mucous hypersecretion

Potential for serious neuropsychiatric events… beware

Used in treatment of anaphylaxis

• Stimulates Beta2-adrenoceptors in broncial smooth muscle → bronchodilation

Used in the treatment of Good Pasture Syndrome

• Cross-links DNA and RNA, inhibiting protein synthesis and cell replication

• aka its cytotoxic

• Meant to deplete autoantibody levels

Has been used to treat malaria and autoimmune diseases such as SLE (skin manifestations and joint pain) and inflammatory arthritis

• MOA unknown

• accumulates in lysosomes and increases their pH → inhibiting cell mediated inflammatroy response

Hydroxychloroquine, Methylprednisolone (a corticosteroid), and Immune suppressants (Rituximab → monoclonal Ab)

2 (or more)

Stopping drug therapy will cause the development of resistance due to high mutation rate

• NRTI - nucleoside reverse transcriptase inhibitors

• NNRTI - non-nucleotide reverse transcriptase inhibitors

• PI - protease inhibitors

• INSTI- integrase strand transfer inhibitors

• Fusion inhibitors

• Entry inhibitors

• PK enhancer

prodrug enters cell

host cell kinase phosphorylates → activation

active drug competes with human nucleotides for a spot in the elongating DNA chain → prevents HIV viral replications

these drugs cannot eradicate the virus from cells that already integrated pro-viral DNA

An NRTI for HIV

• inhibits mitochondrial DNA polymerase gamma

Side effects

• Anemia

• Neutropenia

• Myopathy

An NRTI for HIV

• the ONLY guanosine analoge NRTI

Some are hypersensitive - discontinue immediately, as it can be fatal

The only nontoxic NTRIs for HIV

Most commonly used NRTI for HIV

only nucleotide analog (all others are nucleosides)

Side effects

• Nephrotoxic

• Fanconi syndrome

• Decreases in bone mineral density with chronic use

NRTIs that cause irreverible sensory neuropathy and pancreatitis

overall avoided

2 NRTIs with different MOAs (tenofovir-emtricitabine)

1 NNRTI (etravirine) OR 1 INSTI (dolutegravir)

use when patient is pregnant along with the 2 NRTIs

INSTI for HIV

• Safe for pregnancy!!!

chemical substrates bind to the hydrophibic subunit of the HIV-1 reverse transcriptase, causing noncompetitive inhibition

when used along with NRTIs you achieve synergism

NOT active against HIV-2

NNRTIs that rarely produce life thereating hepatitis or SJS

Autoinducers for metabolism

NNRTIs given with food

PPIs reduce their absorption

Rarely used NNRTI thats dosed at 3x per day

Peptide like chemicals that target protease enzymes, inhibiting them. This interrupts viral cycle and replication (selective →do not target human proteases)

Active against both HIV-1 and HIV-2

end in -navir

Have poor bioavailablitiy and unbearable toxicity

PI for HIV that causes Kidney Stones, cholelithasis, and dyslipidemia

PI for HIV that is often used alongside other PIs

POTENT inhibitor to CYP3A4

increases cholesterol and trigs

An HIV entry inhibitor

binds to chemokine coreceptor 5 (CCR5), preventing HIV outer envelop protein gp120 binding, fusion, and entry

can cause dose dependent orthostatic HTN

An HIV fusion inhibitor

binds to the gp41 subunit of viral envelope, preventing conformational changes requires for fusion of viral and cell membranes

HIV drug class that is widely used in treatment naive patients due to its excellent tolerability, safety, and antireoviral activity

Suffix -gravir

MOA is essentially preventing viral integration into DNA

Murine monoclonal antibody

• all mouse

Displays the most immunogenecity

Chimera monoclonal antibody

• Variable domain is mouse

• Constant domain is human

Humanisitic monoclonal Antibody

• CDR (complementary determininig region) is mouse

• Rest is human

Human monoclonal antibody

• NO mouse component

Displays the least immunogenicity

Conventional hybridoma technology

• risk of severe allergic response

• Cannot interact with human effector molecules

Recombinant protein technology

• Sometimes the body will make anti-( ) Ab in the presense of these mAbs

Recombinant protein technology

• uses only mouse CDRs grafted into human frameworks

Phage display library

• make gene libraries for both Vh and Vl

• Use transgenic animals to make the mAbs (but there is no mouse component of these mAbs)

-cept

• Neutralization

• Opsonization and phagocytosis

• Antibody-dependent cellular cytotoxicity

• Complement activation

  • inflammation

  • opsonization and phagocytoses

  • MAC → cell lysis

mAbs that act directly when binding to cancer specific antigens and induce immunological response (ex, induce apop, inhibit growth, etc)

mAbs that are modified for the delivery of a toxin, radioisotope, cytokine or other active conjugate

bispecific antibodies that can bind with their Fab regions to both antigen and to a conjugate or effector cell (bringing the two together)

• CD antigen → CD20 on B cells, CD52

• VEGF (vascular endothelial growth factor) inhibitors

• EGFR (epidermal growth factor receptor) inhibitors

• Inhibitory receptors → PD-1, CTLA-4

• Chimeric mAb

• Treats chronic lymphocytic leukemia, non-hodgkins lymphoma, transplant rejection, and some autoimmune disorders

• Binds to CD20 on B cells, resulting in activation of the immune system to kill B cells via opsonization, ADCC and CDC

• Result is decreased B cell levels (cancerous and non cancerous)

  • ergo, this drug can treat pretty much any condition that involves issues with B cells (ex, Rhemumatoid Arthritis, Myesthenia gravis, etc)

• Humanisitic mAb

• Treats only Chronic lymphocytic leukemia

• Binds to CD52 on mature lymphocytes, but NOT on the stem cells from which they were derived

• Conjugated Antibody (murine mAb)

• IgG1 in conjunction with the chelator tiuxetan, to which a radioactive isotope is added

• Treats B cell non-Hodgkin lymphoma in patients who dont respond to other therapy

• Recognizes CD20 on cancer cells and delivers radiation that increases antibody killing effect

  • eg , targets CA cells only!

• Humanisitic mAb

• Inhibits VEGF, blocking angiogenesis

• Treats various cancers

• humanisitic mAb

• Binds to EGFR (specifically HER2), which plays a role in normal cell growth and differentiation

• treats breast, stomach, and esophageal cancer

• Cytokine or cytokine receptors

• Adhesion molecules

• CD antigens → CD20, CD2

• B7 (with CTLA-4Ig)

• Cytokine or cytokine receptors

• IgE

• Treat Rheumatioid Arthritis

• Neutralize the activity of TNF-alpha

• Treats RA

• TNF-alpha receptor-Fc fusion protein

Fusion protein consisting of the extracellular domain of CTLA-4 and Fc portion, binds B7 and block the interaction inhibiting T call activation

• supresses inflammation, decreases anti-collaged Ab production, and reduces antigen specific produciton of INF-gamma

• Etanercept (Enbrel) -TNFα receptor-Fc fusion protein

• Ustekinumab (Stelara)-Neutralize the biological activity of IL-12/23 (responsibe for Th1 and Th17 differetiation - limits type IV HST)

• Secukinumab (Cosentyx), Ixekizumab (Taltz) -Neutralize the biologicalactivity of IL-17⍺ (blocks Th17 cells

• Brodalumab (Siliq, Lumicef)-Blocking IL-17R

• Alefacept (Amevive)-Binds T and NK cells via CD2

• Efalizumab (Raptiva)-Direct against leukocyte function antigen-1 (LFA-1)→ interrupt the interaction of LFA with its ligand intracellular adhesion molecule-1 (ICAM-1) (blocks leukocyte migration into tissues)

• Ocrelizumab (Ocrevus)-Binds to CD20, deplete B cells

• Natalizumab (Tysabri)-Binds to the α4 subunit of integrins

  • 1) inhibiting the migration of immune cells into the central nervous system and

  • 2) inhibiting interactions between integrin and its ligands, thereby possiblyreducing immune cell activation and promoting apoptosis of lymphocytes.

• Reslizumab (Cinqaero, Cinqair)-Neutralizes biological activity of IL-5

• Benralizumab (Fasenra)-Blocking the function of IL-5R⍺

• Omalizumab (Xolair)-Selectively neutralizes soluble human IgE

• Anti-SARS-CoV2 mAbs

• Abciximab

  • Target: Platelet glycoproteins IIb/IIIa

  • Clinical use: Antiplatelet agent for prevention of ischemic complications inpatients undergoing percutaneous coronary intervention

• Denosumab

  • Target: RANKL

  • Clinical use: Osteoporosis; inhibits osteoclast maturation (mimicsosteoprotegerin)

• Palivizumab

  • Target: RSV F protein

  • Clinical use: RSV prophylaxis for high-risk infants

Multiple drugs with different mechanisms of action will synergistically by targeting different steps

• decrease chanves of rejection

• decrease in the dose needed for each drug → less side effects

Greater immunosuppression is required for early success than to maintain long-term immunosuppression

Maintence medications are not without side effects, with many of them being dose dependent

inverses of each other

• Antibody therapy

  • T cell depleting agents

    • Polyclonal Abs

    • Monoclonal

  • Non T cell depleting agents

• High doses of maintence medication

• Polyclonal Ab used in immunosuppression

• IgG generated from horses or rabbits immunized with human thymocytes

• binds to multiple targets on t cells, initially inactivating them, then ultimately resulting in their depletion

• Can cause Cytokine release syndrome, esp with the first dose

• antipyretic → Acetaminophen

• antihistamine → Diphenhydramine

• antiinflammatory → cortocosteroid

antiinflammatory agent

• Monoclonal Ab used in immunosuppression

• Binds to CD52

• Results in T Cell depletion

• Same premedication is given as is for polyclonal Abs (three As…) to prevent cytokine release syndrome

• Non T cell depleting immunosuppressant

• Non depleting (monoclonal) antibody against the IL-2R

• inhibition of T cell proliferation and differentiation, but NOT depletion

• No premedications needed

• However, there is a risk for sever acute hypersensitivity

• Calcineurin inhibitors

• T cell costimulation blocker

• mTOR inhibitors

• Antiproliferative/antimetabolites

• Corticosteroids

Works before IL-2 production

Works After Il-2 production

Multimechanisitic

1. Stimulation of T cells

2. increase of intracellular calcium

3. Activation of of calneurin

4. Dephosphorylation of NFAT by Calcineurin

5. Nuclear translocation of active NFAT

6. Transcripton of IL-2

• Calcineurin inhibitor

• Binds to FK-binding protein 12 (FKBP12)

• No IL-2 production

• Side effects

  • Nephrotoxicity

  • HTN, Hyperglycemia, HLD

• Calcineurin inhibitor

• binds to Cyclophilin (CYP)

• No IL-2 production

• Side effects

  • Nephrotoxicity

  • Gingival Hyperplasia, Hirsutism - specific to this drug only

  • HTN, Hyperglycemia, HLD

• A T cell costomulation blocker

• Blocks CD80/86 → preventing costimulation

• Prevents production of IL-2 and T cell activation

• mTOR inhibitors

  • key component of intacellular signaling pathway for cell growth and proliferation

• Inhibition of interleukin-driven T cell proliferation

  • This drug functions AFTER IL-2 is made, just prevents its action

• Antiproliferative immunosuppressant

• Inhibits IMP dehydrogenase → prevents De NNovo purine synthesis

  • No purines → no lymphocyte proliferation

• Antiproliferative immunosuppressant

• Prodrug! Metabolized to 6-marcaptopurine

• Fradulent nucleotide that arrests chain elongation and stops lymphocyte proliferation

most commonly used corticosterioid

• Exhibits anti-inflammatory and immunosuppressive activity by blocking T cell-derived and APC-derived cytokine expression

• Also formes complexes and inhibits other transcription factors such as NFkB

Drugs with a narrow theraputic range and large interpatient variability

rejection (with induction)

Nephrotoxicity (with inhibition)

Rejection (induction)

Myelosuppression (inhibition)

• Anticonvulsants

  • carbamazepine, phenytion, phenobarbital

• St. John’s Wort

Result in transplant rejection due to the failure of drugs like CNIs and mTOR inhibitors

• Macrolide ABX

  • Erythromycin

  • Clarithromycin

• Azole antifungals

  • Fluconazole

  • Itraconazole

  • Ketoconazole

• Grapefruit juice

Result in toxicity due to overactivty of druge like CNIs and mTOR inhibitors

increased side effects (myelosuppression)

metabolizes thiopurines to less active compounds

Greater concentration of thioguanine nucleotides

this results in more side effects with drugs such as azathioprine → myelosuppression

results in Added nephrotoxicity → Both drugs are nephrotoxic

BAD idea! Avoid live vaccines, as they are Live vaccines are contraindicated in immunocompromised patients due to the risk of severe systemic disease

OK to do! Non-live vaccines can be administered in patients on immunosuppressants after the immune system recovers from induction. However, lower response is to be expected. It is always better to complete the vaccinations prior to transplant/immunosuppression.

Results in Risk of rejection → Phenytoin is a CYP inducer → decrease severolimus concentration (remember mTOR inhibitors are CYP substrates) → risk ofrejection