Week 8: Immunopharmacology

Active immunity:

Host produces its own immune response after exposure or vaccination

Passive immunity:

Transfer of antibodies, such as maternal transfer or antibody drugs

Innate immunity:

Fast immune response over hours to days

Low specificity

Antigen-independent

Adaptive/acquired immunity:

Slower immune response over days to weeks; highly specific; antigen-dependent

Primary immunosuppressive drug checkpoints:

Antigen presentation

IL-2 production by T-cells

T-cell activation by IL-2

T-cell metabolism

Why is T-cell activity important in transplant rejection?

Without T-cell recognition, rejection is unlikely

Want to reduce transplant rejection without increasing infection or neoplasm

Corticosteroids:

Immunosuppressants used for acute rejection and medium term prevention

Corticosteroid examples:

Prednisone and dexamethasone

How do corticosteroids suppress immunity?

Decrease circulating macrophages/T-cells and decrease cytokine/MHC expression

What is a dental implication for systemic steroids?

Consult physician for pain producing procedures

Potential for oral disease (allergy, inflammatory, autoimmune)

Dexamethasone dental use:

Mouthwash for oral inflammatory/autoimmune lesions (0.5mg/5ml)

Triamcinolone dental use:

Topical treatment for lesions and ulcers

What are corticosteroid contraindications?

Systemic fungal/viral/bacterial infection, hypersensitivity, planned vaccination while on corticosteroids

What are short-term (less than 4wks) high dose corticosteroid side effects?

Impaired wound healing, periodontal infection, insomnia, mood swings, increased appetite, peptic ulcer

What are long-term corticosteroid side effects?

Osteoporosis, fluid retention, psychosis, immune suppression, adrenal suppression/atrophy, diabetogenic effect, hirsutism

Azathioprine (Azasan):

Antimetabolite immunosuppressant that blocks purine metabolism

How does azathioprine affect lymphocytes?

Lymphocyte specific inhibition because lymphocytes lack purine synthesis salvage pathway

Replaces guanosine with non-active thiosine

What signaling does azathioprine block?

downstream signals from CD28 co-activation of T-cells and anti-apoptotic signaling

What is azathioprine used with?

combintation with Prednisone/corticosteroids + cyclosporine

Is azathioprine effective against existing graft rejection?

No

What are azathioprine adverse effects?

Mild hepatotoxicity, dose-dependent bone marrow suppression, bleeding, malignancy, leukopenia, thrombocytopenia

What is dental use for azathioprine?

Adjunct with prednisone for severe erosive lichen planus, major aphthous stomatitis, erythema multiforme, benign mucous membrane pemphigoid

*Med consult suggested before tx

Mycophenolate mofetil (CellCept):

Antimetabolite immunosuppressant used in combo with glucocorticoids and cyclosporine

What enzyme does mycophenolate inhibit?

Inosine monophosphate dehydrogenase

Why is mycophenolate lymphocyte-specific?

Lymphocytes lack purine synthesis salvage pathway

What are oral ADRs of mycophenolate?

Mouth ulceration, gum hyperplasia, gingivitis, dry mouth, mucocutaneous Candida, dysphagia, nausea/vomiting, stomatitis

What systemic ADRs are associated with mycophenolate?

Myelosuppression, neutropenia, malignancy, teratogenicity

Many drug interactions (many antibiotics)

Calcineurin inhibitors:

Immunosuppressants that prevent calcineurin activation and decrease IL-2 secretion

Calcineurin inhibitor examples:

Cyclosporine (Neoral) and tacrolimus (Protopic)

What immunophilins do calcineurin inhibitors inhibit?

Cyclophilin and FK506-binding protein

How do calcineurin inhibitors affect IL-2?

Decrease nuclear factor activity and reduce IL-2 secretion

Cyclosporine:

Primary immunosuppressant that can be effective as a single agent but is usually used in triple therapy

What are cyclosporine's systemic ADRs?

Nephrotoxicity, hepatotoxicity, malignancy, hypertension, diabetogenic effect

What are oral ADRs of cyclosporine?

Gingival hyperplasia/bleeding, xerostomia, dysphagia, mouth sores, abnormal taste

Why is blood level monitoring important with cyclosporine?

to avoid nephrotoxic levels

Tacrolimus:

Calcineurin inhibitor used for organ rejection prophylaxis and topically for ulcerative lesions

What is a dental use of tacrolimus?

Topical treatment for ulcerative lesions

Why does tacrolimus have many drug interactions?

CYP3A4 metabolism

What are systemic ADRs of tacrolimus?

Nephrotoxicity, hepatotoxicity, neurotoxicity, many other systemic effects

What are oral ADRs of tacrolimus?

Stomatitis, oral candidiasis, dysphagia, esophagitis including ulcerative esophagitis

mTOR inhibitors:

Immunosuppressants that inhibit FK506, prevent mTOR activation, and decrease IL-2 signaling

mTOR inhibitor examples:

Sirolimus (Rapamune) and Everolimus (Afinitor)

What are mTOR inhibitors used for?

Triple therapy, synergy with cyclosporine, acute rejection, moderate-to-strong immunosuppression

What are oral/dental ADRs of mTOR inhibitors?

Mouth ulceration, oral candidiasis, stomatitis, gingival hyperplasia, gingivitis, dysphagia, impaired wound healing and postoperative infection

Do mTOR inhibitors have significant nephrotoxicity?

No significant nephrotoxicity

Why do mTOR inhibitors have many drug interactions?

CYP3A4 metabolism

Polyclonal antibodies:

antibodies raised in rabbit/horse against lymphocyte antigens

Rapid and profound lymphopenia with long half-lives

When are polyclonal antibodies effective?

Steroid resistant rejection

What are 1st dose reactions to polyclonal antibodies?

Anaphylaxis and cytokine release syndrome

*high incidence

Fever, chills, nausea, pulmonary edema, vascular collapse

Monoclonal antibodies:

Antibodies used in combination therapy for many immune indications

Anti-TNF DMARDs:

Infliximab and adalimumab:

Anakinra:

IL-1 receptor antagonist used for rheumatoid arthritis

What monocloncal antibodies are used for renal transplant?

Basiliximab and daclizumab

Anti-IL-2 receptor antibodies

What adverse reaction is associated with monoclonal antibodies?

Cytokine release syndrome

Methotrexate:

Antimetabolite immunosuppressant/anticancer drug also used in rheumatoid arthritis and severe psoriasis

What are methotrexate ADRs?

Bone marrow suppression and teratogenicity

What drugs can increase methotrexate toxicity?

NSAIDs, phenytoin, sulfonamides, penicillins

Cyclophosphamide:

anticancer drug, DNA alkylating

What is cyclophosphamide effective against?

very early acute rejection

What are cyclophosphamide ADRs?

Vomiting, nausea, carcinogenicity

Immunostimulant biologicals:

Cytokines with pharmacologic effects that match biologic effects

What are examples of immunostimulant biologicals?

IFNs, IL-2, IL-11, G-CSF, GM-CSF