BNF - Chapter 8 - Immune system and malignant disease Flashcards
Which immunosuppressant drugs have a role in the management of inflammatory bowel disease?
- Azathiopurine
- Ciclosporin
- Mercaptopurine
- Methotrexate
Other than chronic inflammatory diseases when else are immunosuppressants used?
They are used to suppress rejection in organ transplant recipients and to treat a variety of chronic inflammatory and autoimmune diseases.
What may modification of tissue reactions caused by corticosteroids and other immunosuppressants result in?
The rapid spread of infection
What do antiproliferative drugs do?
Antiproliferative agents, also known as antimetabolites, inhibit cell-cycle pathways to limit T- and B-cell proliferation and thereby reducing the cytotoxic response directed toward the cardiac allograft.
Give a list of some antiproliferative immunosuppressants?
- Azathioprine
-Mercaptopurine - ## Mycophenolate mofetil
What is azathioprine metabolised to?
Mercaptopurine
When azathioprine is given with allopurinol should the dose stay the same?
Doses should be reduced when allopurinol is given concurrently
Which has a more selective mode of action - mycophenolate or azathioprine?
Mycophenolate
Are the corticosteroids immunosuppressants?
Yes they are powerful immunosuppressants
They are used to prevent organ transplant rejection, and in high dose to treat rejection episodes
What inhibitor is ciclosporin?
Calcineurin inhibitor
Is ciclosporin an immunosuppressant?
Yes - it is a potent immunosuppressant which is virtually non-myelotoxic but markedly nephrotoxic
Name another calcineurin inhibitor?
Tacrolimus;
Although not chemically related to ciclosporin it has a similar mode of action and side effects
Is the incidence of neurotoxicity greater with ciclosporin or tacrolimus?
It is greater with tacrolimus than with ciclosporin
Name a non-calcineurin inhibiting immunosuppressant licensed for renal transplantation?
Sirolimus
What is myelosuppression?
Suppression of the immune system
Azathioprine is an immunosuppressant metabolised to?
Mercaptopurine
What are some hypersensitivity reactions of azathioprine?
- malaise
- dizziness
- Vomiting
- Diarrhoea
- Fever
- Myalgia
- rash
- hypotension
- renal dysfunction
What should patients do if they experience any of these hypersensitivity reactions?
Withdraw treatment immediately
What blood disorders can azathioprine cause?
Neutropenia and thrombocytopenia
Neutropenia is dose-dependent
What does the management of neutropenia and thrombocytopenia induced by azathioprine require?
Careful monitoring and dose adjustment
What symptom is common in the early stages of treatment with azathioprine?
- Nausea is common and usually resolves in a few weeks without changing the dose.
With azathioprine how can moderate nausea be managed?
By using divided daily doses, taking doses after food, prescribing antiemetics or temporarily reducing the dose
What pre-screening treatment is important with azathioprine?
The enzyme thiopurine methyltransferase (TPMT) which metabolises thiopurine drugs (azathioprine, mercaptopurine, etc.)
What risk is increased in patients with reduced activity of the enzyme TPMT?
Increases the risk of myelosuppression in patients with reduced activity of this enzyme (TPMT), thus TPMT activity should be measured before starting treatment
Which patients should not receive azathioprine based on their TPMT levels during pre screening?
Patient with absent TPMT activity should not receive this drug, those with reduced TPMT activity may be treated under specialist supervision
what monitoring requirements are there for azathioprine?
Monitor for toxicity throughout the treatment
Monitor full blood count weekly (more frequently with higher doses or if severe hepatic or renal impairment) for the first 4 weeks…. thereafter reduce the frequency of monitoring to every 3 months
• Blood tests and monitoring for myelosuppression are essential in long-term treatment.
Is azathioprine prescribing brand specific?
Yes it is so it should be prescribed by brand
Ciclosporin is a potent immunosuppressant - does it also cause myelosuppression?
Not but it is nephrotoxic (toxic to the kidneys)
Does same brand need to be maintained for ciclosporin?
Yes - patients should be stabilised on a particular brand because switching between formulations without close monitoring can lead to important changes in blood-ciclosporin concentrations
What are the common side effects when ciclosporin is used as an eye drop?
common side effects include eye discomfort and inflammation… as well as blurred vision.
What are the monitoring requirements of ciclosporin?
- blood ciclosporin concentration should be monitored throughout treatment
- Renal function should be monitored - an increase in serum creatinine and urea may call for a dose reduction (in transplant patients) or discontinuation of treatment (in non-transplant patients)
- Blood pressure should be monitored - discontinue if hypertension develops that cannot be controlled with antihypertensive
Blood lipids should be measured before and after the first month of treatment - Monitor liver function
Before starting ciclosporin treatment for psoriasis and eczema how many times should blood pressure and renal function be measured?
Atleast twice
In rheumatoid arthritis - for ciclosporin what other parameter would be monitored?
- Serum creatinine at least twice before treatment.
During treatment, monitor serum creatinine every 2 weeks for the first 3 months and then every month for a further 3 months.
Patients on ciclosporin should be advised to avoid what?
Avoid excessive exposure to UV light, including sunlight.
Is tacrolimus calcineurin inhibitor?
Yes which acts to suppress the immune system
Switching between oral tacrolimus products have been associated with what?
Associated with toxicity and transplant rejection
Do oral tacrolimus need to be prescribed by brand?
YEs to maintain therapeutic response
Give the different brands of tacrolimus and their daily frequency of administration?
daily (once in the morning and once in the evening)
- Modigraf granules make an immediate release oral suspension which is taken TWICE daily (once in the morning and once in the evening)
- Advagraf is a prolonged-release capsule that is taken ONCE daily in the morning.
What has been reported with tacrolimus blood concentrations much higher than the maximum levels in children?
Cardiomyopathy (disease of the heart muscle) has been reported to occur primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels.
For cardiomyopathy risk with tacrolimus what should patients be monitored for?
Patients should be monitored by echocardiography for hypertrophic changes – consider dose reduction or discontinuation if these occur.
Is mycophenolate mofetil a immunosuppressant?
Yes
With mycophenolate what should be measured if there is recurrent infection?
Measure serum immunoglobulin and consider bronchiectasis (abnormal widening of the bronchi causing infection) or pulmonary fibrosis if persistent respiratory symptoms such as cough and dyspnoea (difficulty breathing) develop.
What other counselling should be given to patients taking mycophenolate mofetil?
- patients should be warned to report immediately any signs or symptoms of bone marrow suppression e.g. infection or unexplained bruising or bleeding.
What should be excluded before starting mycophenolate?
- exclude pregnancy in females of child bearing age
- 2 pregnancy tests 8-10 days apart are recommended
- women should use at least 1 form of effective contraception before and during treatment, and for 6 weeks after discontinuation - 2 methods of effective contraception are preferred.
What is multiple sclerosis?
Multiple sclerosis is a chronic, immune-mediated, demyelinating inflammatory condition of the central nervous system, which affects the brain, optic nerves and spinal cord, and leads to progressive severe disability.
What is the pattern of the disease?
Relapsing-remitting multiple sclerosis is the most common pattern of the disease. It is characterised by periods of exacerbation of symptoms (relapses) followed by unpredictable periods of stability (remission).
On average how times a year does it occur?
The severity and frequency of relapses varies greatly between patients, but on average occur once or twice per year.
What does the clinical pattern of multiple sclerosis lead to?
This clinical pattern often develops into secondary-progressive multiple sclerosis, with progressive disability unrelated to relapses.
Most patients develop secondary progressive disease 6–10 years after onset.
What is active disease (multiple sclerosis) defined as?
as at least two clinically significant relapses occurring within the last 2 years.
What is highly active disease characterised as?
by an unchanged/increased relapse rate or by ongoing severe relapses compared with the previous year, despite treatment with interferon beta
What is rapidly-evolving severe relapsing-remitting multiple sclerosis defined as?
By two or more disabling relapses in 1 year and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared with a previous MRI.
Is there a cure for multiple sclerosis?
No there is no cure for this
Which drugs are used in the treatment of multiple sclerosis in England?
- Interferon beta
- Glatiramer Acetate
- Fingolimod
- Natalizumab
What is believed to be a risk factor for developing multiple sclerosis?
Low levels of vitamin D
What are patients with diagnosed multiple sclerosis usually given?
Regular vitamin D after assessment of their serum levels of vitamin D, but there is insufficient evidence to support its use as a treatment for multiple sclerosis.
Patients should not be offered vitamin D solely for the purpose of treating multiple sclerosis.
What is recommended for active relapsing-remitting multiple sclerosis?
. Interferon beta and glatiramer acetate
- Peginterferon beta-1a requires less frequent administration and is available as an alternative to the non-pegylated interferon beta therapies.
Which drugs are preferred options for active disease?
Teriflunomide and dimethyl fumarate are treatment options for patients with active disease. They may be preferred due to their oral route of administration.
More active disease may be treated with what?
with natalizumab or alemtuzumab.
Which is the only one recommended for the treatment of rapidly-evolving severe relapsing-remitting multiple sclerosis?
natalizumab
Which is the only drug licensed to be used in secondary progressive multiple sclerosis?
- Interferon beta 1b
Is there any drugs available for primary progressive multiple sclerosis?
Currently there are no effective disease-modifying treatments licensed for primary progressive multiple sclerosis
Are there any specific treatment for progressive-relapsing multiple sclerosis?
No specific treatment options for this type of multiple sclerosis. None of the currently licensed disease-modifying drugs are recommended in non-relapsing progressive disease.
Other than neurological dysfunction of multiple sclerosis - what are some of the other chronic symptoms?
- chronic symptoms (such as fatigue, spasticity, visual problems, and emotional lability) produce much of the disability in multiple sclerosis.
What can increase the progression of disability in multiple sclerosis?
Smoking - therefore smoking cessation should be encouraged
For suspected relapses what is recommended first line?
Oral methylprednisolone is recommended as the first-line option. Intravenous methylprednisolone should be considered as an alternative if oral methylprednisolone has failed or is not tolerated or if hospitalisation is required.
Are vitamin B12 injections recommended as treatment for fatigue in patients with multiple sclerosis?
No
Which drug is licensed for the improvement of walking in patients with multiple sclerosis?
- Fampridine
NICE do not consider it to be a cost-effective treatment and do not recommend its use.
What factors may aggravate spasticity in multiple sclerosis?
constipation, infection, poor mobility aids, pressure ulcers, posture and pain
What are the first line options of managing spasticity in multiple sclerosis?
- Baclofen
or - Gabapentin (unlicensed)
What are second and third line options for spasticity in multiple sclerosis?
Tizanidine or dantrolene sodium are second-line options; benzodiazepines may be used as third-line therapy and may also be effective in treating nocturnal spasms.
If other treatments are not effective then a 4 week trial of what can be offered?
A 4-week trial of cannabis extract can be offered as adjunctive treatment for moderate to severe spasticity in multiple sclerosis if other pharmacological treatments are not effective.
Is interferon beta a biological medicine?
Yes
What should be noted about prescribing biological medicines?
Biological medicines must be dispensed by brand name
Manufacturer advises to record the brand name and batch number after each administration
What do cytotoxic drugs have?
They have both anti-cancer activity and the potential to damage normal tissue
Are most cytotoxic drug teratogenic?
Yes
What are the pros and cons of combination of cytotoxic drugs?
Combinations of cytotoxic drugs, as continuous or pulsed cycles of treatment, are frequently more toxic than single drugs but have the advantage in certain tumours of enhanced response, reduced development of drug resistance and increased survival. However for some tumours, single-agent chemotherapy remains the treatment of choice.
What are the key points of cytotoxic drug handling guidelines?
Trained personnel should reconstitute cytotoxics
Reconstitution should be carried out in designated pharmacy areas
Protective clothing (including gloves, gowns, and masks) should be worn
The eyes should be protected and means of first aid should be specified
Pregnant staff should avoid exposure to cytotoxic drugs (all females of child-bearing age should be informed of the reproductive hazard)
Use local procedures for dealing with spillages and safe disposal of waste material, including syringes, containers, and absorbent material
Staff exposure to cytotoxic drugs should be monitored
What is the dosing of cytotoxic drugs determined by?
using a variety of different methods including body-surface area or body-weight. Alternatively, doses may be fixed.
Doses may be further adjusted following consideration of a patient’s neutrophil count, renal and hepatic function, and history of previous adverse effects to the cytotoxic drug. Doses may also differ depending on whether a drug is used alone or in combination.
what is oral mucositis - from chemotherapy?
A sore mouth is a common complication of cancer chemotherapy; it is most often associated with fluorouracil, methotrexate, and the anthracyclines.
What advice can you give for oral mucositis?
Good oral hygiene (rinsing the mouth frequently and effective brushing of the teeth with a soft brush 2–3 times daily) is probably beneficial. For fluorouracil, sucking ice chips during short infusions of the drug is also helpful.
Once a sore mouth has developed, treatment is much less effective.
In general, mucositis is self-limiting but with poor oral hygiene it can be a focus for blood-borne infection.
Which mouth wash should be used for oral mucositis?
Saline mouthwashes should be used but there is no good evidence to support the use of antiseptic or anti-inflammatory mouthwashes.
Which patients are at risk of tumour lysis syndrome?
include those with non-Hodgkin’s lymphoma (especially if high grade and bulky disease), Burkitt’s lymphoma, acute lymphoblastic leukaemia and acute myeloid leukaemia (particularly if high white blood cell counts or bulky disease), and occasionally those with solid tumours.
Pre-existing hyperuricaemia, dehydration, and renal impairment are also predisposing factors.
What are the features of tumour lysis syndrome?
Features include hyperkalaemia, hyperuricaemia (see below), and hyperphosphataemia with hypocalcaemia; renal damage and arrhythmias can follow. Early identification of patients at risk, and initiation of prophylaxis or therapy for tumour lysis syndrome, is essential.
Can chemotherapy worsen hyperuriceamia?
Yes - Hyperuricaemia, which may be present in high-grade lymphoma and leukaemia, can be markedly worsened by chemotherapy and is associated with acute renal failure.
What should be started in hyperuricaemia in chemotherapy?
- Allopurinol should be started 24 hours before treating such tumours and patients should be adequately hydrated
The dose of which proliferative immunosuppressants should be reduced if allopurinol is used?
The dose of mercaptopurine or azathioprine should be reduced if allopurinol needs to be given concomitantly.
Which other drug other than allopurinol can be used?
- Febuxostat may also be used and should be started 2 days before cytotoxic therapy is initiated
Which drug is licensed to be used for hyperuricaemia in patients with haematological malignancy?
Rasburicase, a recombinant urate oxidase, is licensed for hyperuricaemia in patients with haematological malignancy.
It rapidly reduces plasma-uric acid concentration and may be of particular value in preventing complications following treatment of leukaemias or bulky lymphomas.
Do all cytotoxic drugs cause bone-marrow supression?
Yes except vincristine sulfate and bleomycin.
Peripheral blood counts should be checked when?
Before each treatment and doses should be reduced or therapy delayed if bone-marrow has not recovered
What should be noted about cytotoxic drugs and active infection?
Cytotoxic drugs may be contra-indicated in patients with acute infection; any infection should be treated before, or when starting, cytotoxic drugs.
What does fever in neutropenic chemotherapy patient (neutrophil count less than 1.06x10^9/Litre) require?
Requires immediate broad-spectrum antibacterial therapy
What is symptomatic anaemia in chemotherapy patients usually treated with?
With red blood cell transfusions.
Is hair loss (alopecia) a complication of cytotoxic drugs?
Yes - it is a common complication, although it varies in degree between drugs and individual patients.
Is there a pharmacological method to prevent alopecia (hair loss) from chemotherapy?
No
Does chemotherapy increase the risk of thromboembolism?
Venous thromboembolism can be a complication of cancer itself, but chemotherapy increases the risk.
Due to teratogenicity what should be excluded before starting cytotoxic drug?
Exclude pregnancy
Contraceptive advice should be given before cytotoxic therapy begins- women of childbearing age should use effective contraception during and after treatment.
Which cytotoxic drugs carry a greater risk for causing permanent male sterility?
Regimens that do not contain an alkylating drug or procarbazine may have less effect on fertility, but those with an alkylating drug or procarbazine carry the risk of causing permanent male sterility (there is no effect on potency).
Pretreatment counselling and consideration of sperm storage may be appropriate.
Are women also equally affected?
No women are less severely affected, although the span of reproductive life may be shortened by the onset of a premature menopause
Is nausea and vomiting common with cytotoxic drugs?
Yes therefore prophylaxis of nausea and vomiting is extremely important
What is classed as acute symptom or delayed nausea and vomiting with chemotherapy?
Symptoms may be acute (occurring within 24 hours of treatment), delayed (first occurring more than 24 hours after treatment), or anticipatory (occurring prior to subsequent doses).
Which are more difficult to treat?
Delayed and anticipatory symptoms are more difficult to control than acute symptoms and require different management.
