Chapter 8: Immune system and malignant disease Flashcards
What do immunosuppressants do?
Suppresses or prevents the immune response
Immunosuppressant uses?
- transplant rejection
- inflammatory diseases e.g. rheumatoid arthritis, severe eczema or IBD
Antiproliferative immunosuppressants?
- azathiopurine
- mercaptopurine
- mycophenolate mofetil
Other immunosuppressants?
- ciclosporin
- tacrolimus
- corticosteroids
What should be avoided with immunosuppressants ?
Live vaccines! - high risk of infections when on immunosuppressants
Azathioprine/mercaptopurine MOA
Mercaptopurine inhibits purine metabolism therefore DNA, RNA and protein synthesis. Azathioprine is metabolised to mercaptopurine
Azathioprine/mercaptopurine side effects?
- hypersensitivity reactions; STOP immediately!; rash, fever, myalgia, arthralgia, malaise, interstitial nephritis, nausea, vomiting and diarrhoea
- bone marrow suppresion: pre-treatment screening for thiopurine methyl transferase. Low enzyme activity = high risk of myelosuppression
Azathioprine/mercaptopurine interactions?
- reduce dose with allopurinol = toxicity
- allopurinol is a xanthine oxidase inhibitor; inhibits metabolism of purines
Mycophenolate mofetil MOA?
Metabolised to mycophenolic acid. A selective mode of action than purine synthesis inhibitors e.g. azathioprine
“Mycophenolate mofetil (MMF, CellCept) is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5’-monophosphate dehydrogenase. MPA depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation.”
Mycophenolate mofetil side effects?
- hypogammaglobinaemia: recurrent infections = measure serum immunoglobulin
- bronchiectasis: respiratory symptoms e.g. cough, dyspnoea
- bone marrow suppression
Mycophenolate mofetil and pregnancy?
GENOTOXIC AND TERATOGENIC
- women: two methods of effective contraception until 6 weeks after discontinuing
- men: use condoms until 90 days after discontinuing OR female partners use effective contraception until 90 days after discontinuing
What is tacrolimus?
Calcineurin inhibitor
Tacrolimus side effects?
- heart = cardiomyopathy e.g. arrhythmias
- kidney = nephrotoxicity
- liver = hepatotoxicity
- bone marrow = blood dyscrasias
- blood = hypertension, hyperglycaemia, hyperuricaemia
- neurotoxicity = headaches and tremors
- eye disorders = blurred vision, photophobia
- skin = rashes, toxic epidermal necrolysis
Tacrolimus patient counselling?
- avoid exposure to sunlight/UV light: use wide spectrum SPF
- diet: avoid high potassium and grapefruit juice = high tacrolimus level
- driving may be affected
MHRA reminder to maintain on the same brand (oral), reports of toxicity and transplant rejection when switching between products
Ciclosporin MOA?
Lowers activity of T cells and their immune responses
Ciclosporin side effects?
- kidneys = nephrotoxicity
- liver = hepatotoxicity
- bone marrow = blood dyscrasias
- blood = lipids (hyperlipidaemia), hypertension, hyperkalaemia and hypOmagnesaemia
- visual disturbances = secondary to benign intracranial hypertension
- gingival hyperplasia
- neurotoxicity
Ciclosporin patient counselling?
- avoid excess sun exposure/UV light: use wide spectrum SPF
- diet: avoid high potassium and grapefruit jucie = high ciclosporin level
MHRA advice: oral ciclosporin, maintain on same brand - switching between can lead to clinically important changes in ciclosporin concentration
Cancer therapy aims?
Curative intent OR prolong life OR palliate symptoms
What is neoadjuvant cancer therapy?
- initial chemotherapy aimed at shrinking the primary tumour
- this makes local therapy less destructive or more effective
What is adjuvant cancer therapy?
- this follows a definitive treatment of the primary disease when there is a high risk of sub-clinical metastatic disease
What are the guidelines for handling cytotoxic drugs?
- trained personnel should reconstitute cytotoxic drugs
- designated pharmacy area for reconstituting cytotoxic drugs
- wear protective clothing and cover eyes
- first aid should be specified
- pregnant staff should avoid exposure to cytotoxic.
- females of child bearing age should be informed of reproductive hazard
- local procedures for spillages and safe waste disposal
- monitor staff exposure
Safe system requirements for cytotoxics?
Chemotherapy is given as a part of a wider pathway of coordinated care by a multidisciplinary team:
- cytotoxic medicines should be prescribed, dispensed and administered according to written protocol or treatment plan
- injectable cytotoxic drugs should only be dispensed if they are prepared for administration
- oral cytotoxic medicines should be dispensed with clear directions for use
Non-specialists and cytotoxic drugs ?
- have access to written protocols or treatment plan when prescribing/administering ongoing oral cytotoxic medicines
- protocols include guidance on monitoring and treatment of toxicity
Dispensing cytotoxic drugs ?
- confirm dose is appropriate
- prescriptions should not be repeated unless specialist instructs
- patient must have written information on their oral anti-cancer regimen which includes treatment plan and monitoring arrangements taken from the original hospital protocol
- pharmacists must have access to this information and to advise from experienced cancer pharmacist in the initiating hospital
Cytotoxic side effects?
- extravasation of IV drugs
- pregnancy and reproductive function
- oral mucositis
- urothelial toxicity
- bone marrow suppression
- nausea and vomiting
- alopecia
- hyperuricaemia
- thromboembolism
Cytoxic drugs and pregnancy and reproductive function?
Most cytotoxic drugs are teratogenic
- exlude pregnancy before treatment
- offer contraceptive advice to men and women
Alkylating drugs and procarbazine:
- permanent male sterility, counsel patient on sperm storage
- women are less affected; early menopause may occur
What side effect does procarbazine have on reproductive function?
- permanent male sterility - counsel on sperm storage
- women less affected - may enter early menopause
What is tumour lysis syndrome?
- caused by rapid destruction of malignant cells (high risk in lymphomas or leukaemias)
- clinical features: hyper K, hyper urea, hyper PO4 and hypo Ca2+
- followed by renal failure and arrthythmias
- at risk patients: renal impairment, dehydration and hyperuricaemia
Thromboembolism cytotoxic side effect?
- malignant disease is a risk factor for venous thromboembolism but cytotoxic drugs also increase this risk
- tamoxifen (also causes endometrial cancer)
- thalidomide/linadamide
Cytotoxic side effect oral mucositis and how to avoid?
- good oral hygiene prevents a sore mouth
- rinse mouth frequently
- use a soft toothbrush 2-3 times daily, suck on ice cubes
- saline mouthwashes
- folinic acid in MTX-induced adverse effects
- anthracyclines
- antimetabolites (methotrexate, fluorouracil, capecitabine)
What is urothelial toxicity?
Urothelial toxicity = haemorrhagic cystitis
- treatment = MESNA
- Cyclophosphamide
Cytotoxic side effect bone marrow suppression?
- all cytotoxic drugs except vincristine and bleomycin
- take FBC before each treatment
- c/i: infections, avoid live vaccines
- treatment: withdraw or reduce dose until bone marrow recovers
- fever with neutropoenia: broad spec antibiotic (filgrastrim) - avoid paracetamol, delays starting antibiotic
- symptomatic iron-deficiency anaemia: erythpoietin or rbc transfusions
Hyperuricaemia cytotoxic side effect?
- present in high grade lymphoma and leukaemia: markedly worsened by chemotherapy and associated with renal failure
TREATMENT - allopurinol 24 hours before treating such tumours. reduce dose of concomitant mercaptopurine/azathioprine
- febuxostat 2 days before if allopurinol contraindicated
- rasburicase for hyperuricaemia associated with blood cancer
Mild emetogenics ? (cytotoxic drugs)
- methotrexate
- flurouracil
- vinca alkaloids
Moderate emetogenics?
- taxanes
- doxorubicin
- cyclophosphamide
- high dose MTX
High emetogenics?
- cisplatin
- high dose cyclophosphamide
Treatment of nausea and vomiting cytotoxic side effect?
- before treatment: lorazepam
Acute symptoms <24 hrs after chemotherapy
- low risk of emesis = dexamethasone or lorazepam
- high risk of emesis = 5-HT3 antagonist
Delayed symtpoms > 24 hours after chemotherapy
- moderately emetgenic drugs = dexamethasone + aprepitant
Alopecia cytotoxic side effect?
- reversible hair loss is a common complication of chemotherapy
- there are no treatments available to prevent it
Extravasation of IV drugs cytotoxic side effect?
- severe local tissue necrosis if they leak from the veins into the surrounding subcutaenous or subdermal tissue
- in worse cases it can lead to amputation
- vinca alkaloids
- anthracyclines
Cytotoxic antibiotics?
- cytotoxic antibiotics are radiomimetics, avoid concomitant radiotherapy = toxicity
- anthracyclines
- antineoplastic antibiotics
- anthacyclines “rubicin”?
- doxorubicin (excreted in bile - reduce dose if high bilirubin)
- epirubicin
- idarubicin
- daunorubicin
Anthracyclines side effects?
- cardiotoxicity (dose related; higher risk if given with herceptin)
- red urine
Liposomal formulations of doxorubicin reduce incidence of cardiotoxicity and extravasation BUT cause:
- hand and foot synfrome: macular, red skin eruptions
- prevention: cool hands and feet and avoid socks and gloves for 4-7 days after treatment
What is given to treat anthracycline-indiced side effects?
DEXRAZOXANE
Antineoplastic antibiotics?
- bleomycin
Antineoplastic antibiotics side effects?
- pulmonary fibrosis = basal lung crepitations
- respiratory failure in anaesthesia
- hypersensitivity = chills and fever (prevention: IV hydrocortisone)
- dermatological toxicity = hyperpigmentation, sclerotic plaques
What are vinca alkaloids?
- vincristine
- vinblastine
- vindesine
- vinflunine
- vinorelbine
Vinca alkaloids route of administration?
IV ONLY - never give intrathecally = fatal neurotoxicity
NPSA alert: aduilt and teenagers unit recieve doses in 50ml mini bag
- childrens unit recieve doses by syringe
Vinca alkaloids side effects?
- CNS toxicity (peripheral/autonomic neuropathy)
Antimetabolites ?
- methotrexate (MTX)
- capicitabine (pro drug of 5-FU)
- fluorouracil (5-FU)
Antimetabolites side effects?
- oral mucositis
- myelosuppression
- folinic acid speeds up recovery in MTX side effects and overdose
Alkylating drugs ?
- cyclophosphamide (causes urothelial toxicity)
- carmustine
- lomustine
- mephalan
- chlorambucil
- ifosfamide
Alkylating drugs side effects?
- permanent male sterility
- non-lymphocytic leukaemia
Aromatase inhibitors?
- anastrazole
- letrozole
Not for premenopausal women
- aromatase inhibitors are “anti-oestrogens”
Taxanes?
Paclitaxel
Taxanes side effects?
- cardiac disease
- pneumonitis
- sepsis
