immunotherapeutic drugs Flashcards
immunity
1) host response to external challenge
2) innate and acquired
3) vaccination
4) maternal transfer
5) antibodies as drugs
6) prophylactic or therapeutic
innate
1) hours, days
2) low specificity
2) antigen dependent
adaptive
1) days to weeks
2) highly specific
3) antigen dependent
rejection and immunosupression
1) immunosuppressive
- corticosteroids, mTOR inhibs, calcineurin inhibs, anti-proliferatives, anti-metabolites
2) antibodies
3) immunostimulants
med consultation
1) especially in organ transplant patients
primary drug checkpoints
1) most drugs interact with t cell response
2) APC
3) autocrine production of IL-2
corticosteroids
1) prednisone, dexamethasone
- receptor bound to steroid activates DNA to make inhibitor of NFkappaB (IkappaB)
2) acute rejection - medium term prevention
- for organ transplantation
3) circulating macrophage and T cells (downregulates)
4) cytokine and MHC expression (Down)
5) IL-2, TNF production is inhibited
corticosteroid dental implications
1) allergic, inflammatory, or autoimmune diseases
2) systemic steroid - consult PP
- only for pain producing procedures
3) dexamethasone for mouthwash
4) triamcinolone topical for lesions and ulcers
5) contraindication
- systemic fungal, viral, bacterial infection, hypersensitivity, patients planning vaccination
corticosteroid side effects
1) short term (<4 weeks) high dose
- impaired wound healing, perio infection, insomnia, mood swings, increased appetite, peptic ulcer
2) long term
- osteoporosis, fluid retention, psychosis, suppress immune system, adrenal suppression, atrophy, diabetogenic, hirsutism
glucocorticoids
Phosphoenylpyruvate carboxykinase (PEPCK) is reciprocally upregulated in liver and
downregulated in adipose by glucocorticoids. This results in a buildup of free fatty acids
in the blood, which in turn result in insulin resistance and increase gluconeogenesis
azathioprene
1) blockade of purine metabolism
2) Lymphocyte-specific inhibition lacking
purine synthesis salvage pathway
3) Blocks downstream signals from CD28 co-
activation of T-cells and also directly
inactivates anti-apoptotic signal
Azathioprine
Indications and adverse effects
Used in combination with prednisone or
corticosteroids plus cyclosporine
* Ineffective against existing graft rejection
* Mild hepatotoxicity
* Dose dependent bone marrow suppression
* Bleeding possible
* Malignancy, leukopenia,
thrombocytopenia
- generally, inhibition of immune system means less ability to find malignancy
- altered the DNA in some form, but it can replicate and cause downstream issues
Azathioprine
Dental use
Adjunct with prednisone for managing severe
erosive lichen planus, major aphthous
stomatitis, erythema multiforme, and benign
mucous membrane pemphigoid
* Special protection and handling required
* Remember consult suggested before
treatment of patients taking azathioprine
Azathioprine
Dental use
Adjunct with prednisone for managing severe
erosive lichen planus, major aphthous
stomatitis, erythema multiforme, and benign
mucous membrane pemphigoid
* Special protection and handling required
* Remember consult suggested before
treatment of patients taking azathioprine
Mycophenolic acid
Mycophenolate mofetil (CellCept)
Used in
combination with
glucocorticoids
and cyclosporine
* Inhibits inosine
monophosphate
dehydrogenase
* Specific for
lymphocytes as
they lack purine
synthesis salvage
pathway
- inhibits something that makes GTP
Mycophenolic acid
Indications and adverse effects
Prophylactic protection against renal and liver
transplant rejection but also recurrent acute rejection
* Oral ADRs: Mouth ulceration, gum hyperplasia,
gingivitis, dry mouth, mucocutaneous Candida,
dysphagia, nausea, vomiting and stomatitis,
diarrhoea, cramps
* Myelosuppression, neutropenia, malignancy,
teratogenic
* Many drug interactions including some antibiotics
Calcineurin inhibitors
1) Cyclosporine (Neoral) & Tacrolimus (Protopic)
2) inhibit synthesis of IL-2, so therefore, inhibit T-cell activity (They cannot stimulate themselves)
3) inhibition of FK506 binding protein
- prevents calcineurin activation of NFAT
- IL-2 therefore is no produced
Cyclosporine
Indications and adverse drug reactions
Primary drug, cyclosporine effective as single agent,
both normally used in triple therapy
* Nephrotoxic, hepatotoxic, malignancy, hypertension
and diabetogenic
* Oral ADRs: Gingival hyperplasia and bleeding,
xerostomia, dysphagia, mouth sores, abnormal taste
* Blood level monitoring essential to avoid nephrotoxic
levels
tacrolimus
Indications, ADR and dental use
Organ rejection prophylaxis in combination
with glucocorticoids, AZA and MMF
* Dental use: Topical for ulcerative lesions
* Cytochrome P3A4 metabolism so many
potential drug interactions
* Adverse effects: Nephrotoxicity, Hepatotoxicity,
Neurotoxicity, many other systemic effects
* Oral ADRs: Stomatitis, oral candidiasis,
dysphagia, and esophagitis (including
ulcerative)
mTOR inhibitors
1) Sirolimus (Rapamune) & Everolimus (Afinitor)
2) inhibit FK506
- prevent activation of mTOR
- prevent IL-2 signal pathway
mTOR inhibitor
Indications
Used in triple therapy, show synergy with
cyclosporine
* Useful against acute rejection
* Moderate to strong immunosuppression
mTOR inhibitors
Dental and other adverse reactions
Mouth ulceration, oral candidiasis, stomatitis,
gingival hyperplasia, gingivitis, and dysphagia,
impaired wound healing, post-operative
infection. No significant nephrotoxicity.
* Medical consult advised
* Cytochrome P450 3A4 metabolism – many drug
interactions
Polyclonal antibodies
Raised in rabbit or horse against lymphocyte
antigens
* Rapid and profound lymphopaenia, long half
lives
* Effective in steroid resistant rejection
* High incidence of anaphylaxis and cytokine
release syndrome at 1st dose
* Fever, chills, nausea
* Pulmonary edema and vascular collapse
Monoclonal antibodies
Used in combination therapy - many
indications
* DMARDS: Infliximab, Adalimumab - anti-TNF
* Anakinra –IL-1 receptor antagonist for RA
* Renal transplant: Basiliximab and Daclizumab
– anti-IL-2r
* Cytokine release syndrome
Methotrexate – anti-metabolite
Anti-cancer drug, also used in rheumatoid arthritis,
severe psoriasis
– Bone marrow suppression and teratogenic
– Toxicity may be increased by NSAIDS, phenytoin,
sulfonamides, penicillins (renal clearance)
toxic!!! not used much
Cyclophosphamide
Anti-cancer drug, DNA alkylating
– Effective against very early acute rejection
– Vomiting, nausea, carcinogenic
toxic!! not used much
be alert for
Periodontal infections
* Yeast infections
* Viral infections
* Periapical problems, impacted teeth, poorly done endodontic procedures,
oral ulcerations
preventative precautions
Prior to organ transplant or when patient is most immunocompetent,
consider aggressive dental therapy to remove / resolve any possible
dental problems, i.e. scale / root plane for periodontal disease, extract
impacted teeth, complete any needed or expected endodontic
procedures. Consider extracting teeth with compromised endodontic
prognosis.
* Good oral hygiene.
* Prophylaxis for viral and fungal infections.
Patient told to alert dentist or physician at first sign of any infection
From Clinic Handbook for Immunosuppressed Patients
Immunostimulant biologicals
Cytokines – Pharmacological effects same as
biological effects
* Interferons (IFN), Interleukins -2 and -11 (IL-2,
IL-11), granulocyte and granulocyte/macrophage
colony stimulating factors (G-CSF and GM-CSF)
* Increase T-cell activity, anti-viral, promote bone
marrow activity, stimulate platelet production
* Hypersensitivity and anaphylaxis, IFNs: psychiatric
disorders, G-CSF: respiratory distress syndrome,
splenic rupture
Summary
Reduction in transplant rejection without increase in infection
or neoplasm
* Immunosuppression via interference of, primarily, T-cell
activities: without T-cell recognition rejection is unlikely
* Blood monitoring required to establish active concentrations
for some drugs
* Generally triple or quadruple drug therapy
* Drug:Drug interference in cytochrome pathways in particular
