immunotherapeutic drugs

Question 1

immunity

Answer 1

1) host response to external challenge
2) innate and acquired
3) vaccination
4) maternal transfer
5) antibodies as drugs
6) prophylactic or therapeutic

Question 2

innate

Answer 2

1) hours, days
2) low specificity
2) antigen dependent

Question 3

adaptive

Answer 3

1) days to weeks
2) highly specific
3) antigen dependent

Question 4

rejection and immunosupression

Answer 4

1) immunosuppressive
- corticosteroids, mTOR inhibs, calcineurin inhibs, anti-proliferatives, anti-metabolites
2) antibodies
3) immunostimulants

Question 5

med consultation

Answer 5

1) especially in organ transplant patients

Question 6

primary drug checkpoints

Answer 6

1) most drugs interact with t cell response
2) APC
3) autocrine production of IL-2

Question 7

corticosteroids

Answer 7

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

Question 8

corticosteroid dental implications

Answer 8

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

Question 9

corticosteroid side effects

Answer 9

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

Question 10

glucocorticoids

Answer 10

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

Question 11

azathioprene

Answer 11

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

Question 12

Azathioprine
Indications and adverse effects

Answer 12

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

Question 13

Azathioprine
Dental use

Answer 13

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

Question 14

Azathioprine
Dental use

Answer 14

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

Question 15

Mycophenolic acid
Mycophenolate mofetil (CellCept)

Answer 15

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

Question 16

Mycophenolic acid
Indications and adverse effects

Answer 16

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

Question 17

Calcineurin inhibitors

Answer 17

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

Question 18

Cyclosporine
Indications and adverse drug reactions

Answer 18

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

Question 19

tacrolimus
Indications, ADR and dental use

Answer 19

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)

Question 20

mTOR inhibitors

Answer 20

1) Sirolimus (Rapamune) & Everolimus (Afinitor)
2) inhibit FK506
- prevent activation of mTOR
- prevent IL-2 signal pathway

Question 21

mTOR inhibitor
Indications

Answer 21

Used in triple therapy, show synergy with
cyclosporine
* Useful against acute rejection
* Moderate to strong immunosuppression

Question 22

mTOR inhibitors
Dental and other adverse reactions

Answer 22

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

Question 23

Polyclonal antibodies

Answer 23

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

Question 24

Monoclonal antibodies

Answer 24

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

Question 25

Methotrexate – anti-metabolite

Answer 25

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

Question 26

Cyclophosphamide

Answer 26

Anti-cancer drug, DNA alkylating
– Effective against very early acute rejection
– Vomiting, nausea, carcinogenic

toxic!! not used much

Question 27

be alert for

Answer 27

Periodontal infections
* Yeast infections
* Viral infections
* Periapical problems, impacted teeth, poorly done endodontic procedures,
oral ulcerations

Question 28

preventative precautions

Answer 28

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

Question 29

Immunostimulant biologicals

Answer 29

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

Question 30

Summary

Answer 30

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