Immune Response Flashcards
Which drugs are used in the treatment of IBD? (4)
- Azathioprine
- Cyclosporin
- Mercaptopurine
- MTX
(PLUS steroids and aminosalicylic acid derivatives: mesalazine and sulfasalazine)
*folic acid should be given to reduce the possibility of MTX toxicity (usually given weekly on a different day to MTX)
What are the applications of immunosuppressant therapy? (3)
- Suppression of transplant rejection
- Chronic inflammatory conditions
- Chronic autoimmune conditions
Which immunosuppressant drugs are considered anti-proliferative? (2)
- Azathioprine (metabolized to mercaptopurine)
2. Mycophenolate mofetil
Which immunosuppressant drugs are calcineurin inhibitors? (2)
- Cyclosporin
2. Taxrolimus
Solid organ transplant patients are maintained on drug regimens, which may include which drugs? (6)
- Azathioprine
- Mycophenolate mofetil
- Cyclosporin
- Tacrolimus
- Corticosteroids
- Sirolimus
Choice is dependent on the type of organ, time after transplantation, and clinical condition of the patient
Modification of tissue reactions caused by corticosteroids and other immunosuppressants may result in the rapid _______________
spread of infection
Corticosteroids may suppress clinical signs of _____________ and allow diseases such as _____________ or ____________ to reach an advanced stage before being recognized
infection
septicaemia
tuberculosis
Wherever possible, immunisation or additional booster doses for individuals with immunosuppression should be carried out either before __________________ occurs or deferred until _________________ has been seen
immunosuppression
an improvement in immunity
Azathioprine is widely used for _________________ and it is also used to treat a number of auto-immune conditions, usually when _______________ therapy alone provides inadequate control. It is metabolised to mercaptopurine, and doses should be reduced when allopurinol is given concurrently
transplant recipients
corticosteroid
Azathioprine is widely used for transplant recipients and it is also used to treat a number of auto-immune conditions, usually when corticosteroid therapy alone provides inadequate control. It is metabolised to ______________, and doses should be reduced when ____________ is given concurrently
mercaptopurine
allopurinol
Azathioprine is widely used for transplant recipients and it is also used to treat a number of auto-immune conditions, usually when corticosteroid therapy alone provides inadequate control. It is metabolised to mercaptopurine, and doses should be ________________ (increased/reduced) when allopurinol is given concurrently
Reduced
Mycophenolate mofetil is metabolised to mycophenolic acid which has a more selective mode of action than ________________.
azathioprine
Both anti proliferative immunosuppressants
Compared to azathioprine, mycophenolate mofetil is associated with an increased rate of ______________ and a lower rate of _______________
Opportunistic infections (particularly due to tissue-invasive CMV)
Acute transplant rejection
Prednisolone is widely used in oncology. It has a marked ______________ effect in acute lymphoblastic leukaemia, Hodgkin’s disease, and the non-Hodgkin lymphomas. It also has a role in ______________ when it may enhance ______________ and produce a sense of ______________.
antitumour
the palliation of symptomatic end-stage malignant disease
appetite
well-being
The corticosteroids are also powerful _______________. They are used to prevent organ transplant rejection, and in high dose to treat rejection episodes
immunosuppressants
Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant which is virtually non-_______toxic but markedly _______toxic
myelo
nephro
Cyclosporin has an important role in organ and tissue transplantation, for prevention of graft rejection following bone marrow, kidney, liver, pancreas, heart, lung, and heart-lung transplantation, and for prophylaxis and treatment of _____________ disease.
graft-versus-host
Tacrolimus is also a calcineurin inhibitor. Although not chemically related to ciclosporin it has a similar mode of action and side-effects, but the incidence of _______________ appears to be greater; _______________ has also been reported
neurotoxicity
cardiomyopathy
*Disturbance of glucose metabolism also appears to be significant
Sirolimus is a non-calcineurin inhibiting immunosuppressant licensed for ___________ transplantation
renal
Basiliximab is used for _______________ of acute rejection in allogeneic renal transplantation. It is given with ciclosporin and corticosteroid immunosuppression regimens; its use should be confined to specialist centres
prophylaxis
Belatacept is a fusion protein and co-stimulation blocker that prevents __________ activation; it is licensed for prophylaxis of graft rejection in adults undergoing renal transplantation who are seropositive for the Epstein-Barr virus
T-cell
________________ is a fusion protein and co-stimulation blocker that prevents T-cell activation; it is licensed for prophylaxis of graft rejection in adults undergoing renal transplantation who are seropositive for the Epstein-Barr virus
Belatacept
What is the mechanism of action of ciclosporin?
Inhibits calcineurin, thereby reducing IL-2 release and inhibiting production of lymphokines and the cell-mediated immune response
What are the licensed indications of ciclosporin? (8)
- Severe UC refractory to CS
- Severe active RA
- Severe atopic dermatitis (short term, where conventional therapy has failed)
- Severe psoriasis (where conventional therapy has failed)
- Organ and bone-marrow transplantation (used alone)
- Prevention of graft-versus-host disease
- Nephrotic syndrome
- Severe keratitis in dry eye disease that has not responded to treatment with tear substitutes
Are ciclosporin brands interchangeable?
No; switching between formulations without close monitoring may lead to clinically important changes in blood cyclosporin concentration
What are the contraindications to using ciclosporin? (5)
When used by eye:
- Active or suspected ocular or peri-ocular infections
- Ocular or peri-ocular malignancies or pre-malignant conditions
When used systemically:
- Malignancy
- Uncontrolled HTN
- Uncontrolled infection
What are the adverse effects associated with ciclosporin? (11)
- Nephrotoxicity
- Hepatotoxicity
- Fluid retention
- HTN
- Hyperkalemia
- Hypertrichosis
- Gingival hyperplasia
- Tremor
- Impaired glucose tolerance
- Hyperlipidemia
- Increased susceptibility to infection
(Interestingly for an immunosuppressant, ciclosporin is noted by the BNF to be ‘virtually non-myelotoxic’)
https://www.passmedicine.com/review/textbook.php?s=Cyclosporin
In psoriasis, exclude _________________ before starting ciclosporin
malignancies (including those of skin and cervix);
(biopsy any lesions not typical of psoriasis) and treat patients with malignant or pre-malignant conditions of skin only after appropriate treatment (and if no other option). Discontinue if lymphoproliferative disorder develops.
Is ciclosporin safe to use during pregnancy and breastfeeding?
Avoid unless potential benefit outweighs the risk
Is ciclosporin safe to use in patients with hepatic and/or renal impairment?
Caution in severe hepatic impairment due to risk of increased exposure (consider dose reduction and monitor blood level until stable)
Avoid if baseline renal function is impaired (non-renal transplant patients)
What are the monitoring requirements for patients taking systemic ciclosporin? (11)
- Monitor whole blood ciclosporin concentration (trough level dependent on indication)
- Dermatological and physical examination including BP and renal function at least twice before starting treatment for psoriasis or atopic dermatitis
- monitor liver function if concomitant NSAIDs given
- monitor serum K, especially in renal dysfunction (risk of hyperkalemia)
- monitor serum magnesium
- measure blood lipids before treatment and after the first month of treatment
- investigate lymphadenopathy that persists despite improvement in atopic dermatitis
- monitor kidney function (dose dependent in crease in serum Cr and urea during first few weeks may necessitate dose reduction in transplant patients or discontinuation in non-transplant patients)
- monitor BP (discontinue if HTN develops)
- in long-term management of nephrotic syndrome, perform renal biopsies yearly
- in RA, measure serum Cr at least twice before treatment and every 2 weeks for the first 3 months, then every month for a further 3 months, then every 4-8 weeks
What advice should be given to patients and carers regarding ciclosporin? (3)
- Should be counseled to avoid using different formulations of ciclosporin
- Avoid excessive exposure to UV light including sunlight (in psoriasis and atopic dermatitis, avoid use of UVB and PUVA)
- When taking ciclosporin by eye, increased risk of blurred vision may affect ability to drive and perform skilled tasks
What are the indications of mycophenolate mofetil?
Prophylaxis of acute rejection in renal, cardiac, and hepatic transplantation (in combination with a CS and ciclosporin)
Is mycophenolate mofetil use associated with increased risk of malformations or miscarriage in pregnancies where the father was taking mycophenolate medicines?
No, however they are genotoxic and a risk cannot be fully excluded. Therefore, male patients or their female partner should use effective contraception during treatment and for 90 days after discontinuation
Mycophenolate should be used with caution in which patients? (6)
- Patients with GI disease (due to increased risk of hemorrhage, ulceration and perforation)
- Children (higher incidence of side effects)
- Patients with delayed graft function
- Elderly
- Patients with increased susceptibility to skin cancer (avoid exposure to strong sunlight)
- Patients taking other immunosuppressants (increased risk of hypogammaglobulinemia or bronchiectasis)
Measure serum immunoglobulin levels if recurrent infections develop in patients taking mycophenolate and consider _______________ or ______________ if persistent respiratory symptoms such as cough and dyspnoea develop
bronchiectasis
pulmonary fibrosis
What is the mechanism of action of mycophenolate mofetil (MMF)?
Blocks purine synthesis by inhibition of IMPDH thereby inhibiting proliferation of B and T cells
Wha are the common or very common side effects of mycophenolate? (26)
- Acidosis
- Alopecia
- Anemia
- Decreased appetite
- Arthralgia, gout
- Bone marrow disorders
- Constipation, diarrhea, GI discomfort and hemorrhage, burping
- Chills, fever
- Cough, dyspnea
- Depression, anxiety
- Neoplasms
- Drowsiness, headache, malaise, confusion
- Dyslipidemia
- Electrolyte imbalance, hyperuricemia, edema
- Hyperglycemia
- HTN, hypotension
- Increased risk of infection, sepsis
- Insomnia
- Leukocytosis, leukopenia, thrombocytopenia
- Oral disorders
- Pancreatitis
- Paresthesias
- Renal impairment
- Respiratory disorders
- Seizure, tremor
- Weight loss
Is mycophenolate safe to use in pregnancy and breastfeeding?
No; Women should use at least 1 method of effective contraception before and during treatment, and for 6 weeks after discontinuation—2 methods of effective contraception are preferred. Male patients or their female partner should use effective contraception during treatment and for 90 days after discontinuation
*2 pregnancy tests 8-10 days apart are recommended before beginning treatment
Congenital malformations and spontaneous abortions reported when used in pregnancy
Avoid in breastfeeding
What are the monitoring requirements for patients taking mycophenolate?
Monitor full blood count every week for 4 weeks then twice a month for 2 months then every month in the first year
*consider interrupting treatment if neutropenia develops
What advice should be given to patients and careers regarding mycophenolate? (3)
- Ensure female patients understand the need to comply with the pregnancy prevention advice AND advise them to seek immediate medical attention if there is a possibility of pregnancy
- male patients planning to conceive children should be informed of the implications of both immunosuppression and the effect of the prescribed medications on the pregnancy
- Patients should be warned to report immediately any signs or symptoms of bone marrow suppression e.g. infection or inexplicable bruising or bleeding
Compared to ciclosporin, tacrolimus is associated with a lower incidence of ____________, ___________, and ____________, but a higher incidence of ______________ and ______________
Acute rejection
HTN
Hyperlipidemia
Impaired glucose tolerance
DM
What are the major contraindications to using topical tacrolimus? (7)
- Application to malignant or potentially malignant skin lesions
- Application under occlusion
- Avoid contact with eyes and mucus membranes
- Congenital epidermal barrier defects
- Generalized erythroderma
- Immunodeficiency
- Infection at treatment site
What is the mode of action of tacrolimus?
Inhibits calcineurin to down-regulate T cell activity and cell-mediated immune activity
_______________ has been reported to occur primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels.
Cardiomyopathy; Patients should be monitored by echocardiography for hypertrophic changes—consider dose reduction or discontinuation if these occur
Tacrolimus is contraindicated in patients with a history of hypersensitivity to _________________
Macrolides
Is tacrolimus safe to use in pregnancy and breastfeeding?
Avoid in both unless benefits outweigh risks. Crosses the placenta and increases risk of premature delivery, intra-uterine growth restriction, and hyperkalemia
Can tacrolimus be prescribed in patients with hepatic impairment?
Caution in severe impairment; consider dose reduction.
After initial dosing, and for maintenance treatment, tacrolimus doses should be adjusted according to ________________
whole-blood concentration
What monitoring is required for patients taking tacrolimus? (5)
- Monitor whole blood-tacrolimus trough concentration (especially during episodes of diarrhea)
- Monitor BP
- ECG (for hypertrophic changes, risk of cardiomyopathy)
- Fasting blood glucose concentration
- Hematological and neurological (including visual) and coagulation parameters, electrolytes, hepatic and renal function
Effective contraception must be used during treatment and for 12 weeks after stopping ________________
Sirolimus
Monitor whole blood-sirolimus trough concentration (_______________ patients may require higher doses)
Afro-Caribbean
What 3 things need to be monitored when giving tacrolimus with ciclosporin?
- Kidney function
- Lipids
- Urine proteins
