2 - Cytotoxic Agents Flashcards
Cytotoxic agents can be categorised into anti metabolites and alkylating agents
True
The general risks associated with cytotoxic agents are carcinogenesis, teratogenesis, and myelosuppression and an increased potential for infection
True
Cytotoxic agents modulate the behaviour of cells through inhibition of growth and development
True
Anti metabolites are cell cycle specific and mimic the DNA nucleotides, and are most active during the S phase when DNA is being synthesised
True (S “synthesis” phase)
G1 = preparing the cell for DNA reproduction
S = DNA synthesis
G2 = interphase for preparation for division
M = “mitosis” cell division
G0 (some cells) = resting phase awaiting to re-enter cell cycle
The anti metabolites are methotrexate, azathioprine, mycophenolate, topical 5-fluorouracil, thioguanine and hydroxyurea
True
Cyclophosamide, chlorambucil and melphalan are alkylating agents
True
Alkylating agents are independant of the cell cycle
True (exert effect by direct damage to DNA through physiochemical interactions I.e. Alkylation, cross-linking, carbamylation which are cell cycle independent)
Patients using cytotoxic agents should be given general instructions on bleeding risks
True (thrombocytopenia from myelosuppression)
Thioguanine is an antimetabolite from the thioguanine family with a mechanism of action similar to Azathioprine
True
Thioguanine is a not a first line agent in psoriasis
True (third line agent in psoriasis)
Thioguanine is metabolised by the liver and converted to 6-thioguanilyic acid, which is then further converted to di- and triphosphates
True
Thioguanine and hydroxyurea are both renally excreted
True (similar to methotrexate)
Thioguanine has an unpredictable absorption pattern
True
Thioguanine is metabolised by thiopurine methyltransferase (TPMT) and not by xanthine oxidase
True (contrary to Azathioprine which is degraded by both enzyme pathways, Thioguanine is metabolised by TPMT only and so TPMT is more important in its detoxification)
Thioguanine may be administered concurrently with allopurinol (xanthine oxidase inhibitor) without the need for dose reduction
True (xanthine oxidase is not involved in the metabolism of Thioguanine)
Aminosalicylates use should be minimised or avoided in patients on Thioguanine
True (aminosalicylates may inhibit TPMT activity which is involved in metabolism of Thioguanine)
Thioguanine is a prodrug that yields nucleoside analogs which is then converted to nucleotides and incorporated into cellular DNA during the S phase of the cell cycle
True (This produces cytotoxic effects via apoptosis of activated T lymphocytes and decreased T lymphocyte counts in skin lesions)
Myelosuppression and GI side effects are the most common adverse effects in Thioguanine use
True
Thrombocytopenia is an early indicator of myelosuppression in patients using Thioguanine
True
Thioguanine does not usually need to be discontinued due to GI side effects
True (GI adverse effects are usually tolerated without drug discontinuance)
Thioguanine is less hepatotoxic than methotrexate (another antimetabolite agent)
True (Unlike Methotrexate, Thioguanine is not considered particularly hepatotoxic though there have been rare cases of hepatic veno-occlusive disease)
TPMT levels should be considered before starting Thioguanine
True (TPMT levels may guide selection of an adequate starting dose and improves Thioguanine dosing)
Hydroxyurea is a third line agent for psoriasis
True
Hydroxyurea is well absorbed though the metabolism is incompletely understood
True
Patient with renal impairment are more susceptible to hydroxyurea toxicity
True (80% of the drug is excreted through the kidneys)
Hydroxyurea impairs DNA synthesis through inhibition of ribonucleotide diphosphate reductase which reduces nucleotides to deoxynucleotides and limits the supply of DNA bases available for synthesis, resulting in strand breakage and cell death
True
Hydroxyurea prevents cells from repairing damage due to UV or ionising radiation
True
Hydroxyurea is most effective in cells with a high proliferative index, preferentially concentrated within leukocytes
True
Hydroxyurea is relatively contraindicated in patients with bone marrow suppression I.e. Leukopenia, thrombocytopenia, severe anaemia
True (relatively contraindicated in haematologic disorders)
Myelosuppression is the most common adverse effect with hydroxyurea use (anaemia > leukopenia > thrombocytopenia)
True
Mild megaloblastic changes on FBC are common among patients receiving hydroxyurea but is not a reason for discontinuance of the drug
True
N.B. Megaloblastic changes may also be seen with folate supplementation
Dyspepsia may occur with hydroxyurea
True (hydroxyurea can be taken with food, milk or antacids if this occurs)
Hydroxyurea is the most common cause of a drug-induced dermatomyositis-like eruption
True
Hydroxyurea may cause a lichenoid drug eruption and drug-induced lupus
True
Hydroxyurea may cause leg ulcers
True
Hydroxyurea may cause hyperpigmentation of the skin and nails
True
Hydroxyurea may cause limited and reversible alopecia
True
Hydroxyurea may cause photosensitivity and radiation recall
True
Hydroxyurea and its link to non-melanoma skin cancers is unclear
True (reported as an association but confounding factors exist and the degree of risk is unclear although close surveillance for non-melanoma skin cancers is indicated)
Hydroxyurea should not be administered with other myelosuppression agents
True (added bone marrow toxicity with concurrent use of other myelosuppressive agents)
Cyclophosphamide and chlorambucil are derivatives of nitrogen mustard which act independently of the cell cycle
True
In dermatology, Cyclophosphamide is primarily used in the treatment of immunobullous disorders and vasculitis
True
Cyclophosphamide is metabolised by the CYP 450 system in the liver
True
Chronic liver disease such as cirrhosis may prolong the plasma half life of cyclophosphamide due to decreased CYP 450 activity
True
Cyclophosphamide is a prodrug that is first converted in the liver to 4-hydroxycyclophosamide (an inactive metabolite) that exists in equilibrium with Aldophosamide which diffuses directly into cells but is not directly cytotoxic; Aldophosamide is then converted to the directly cytotoxic active metabolite phosphoramide mustard and acrolein
True
Acrolein, a by-product from the cleavage of Aldosphosphamide (yielding the toxic active metabolite phosphoramide mustard and acrolein) is highly reactive and enhances cellular damage by depleting glutathione stores
True
Aldophosamide (a molecule that exists in equilibrium with 4-hydroxycyclophosphamide, the first inactive metabolite of cyclophosphamide) may be converted by aldehyde dehydrogenase to a second inactive metabolite (carboxyphosphamide)
True
Cyclophosphamide has a greater effect on B lymphocytes than T lymphocytes
True (Unlike other immunosuppressive agents with mainly affect T lymphocytes)
Cyclophosphamide has a greater effect on suppressor T cells than helper T cells
True (unlike other immunosuppressive agents which inhibit cytokines produced by T helper cells)
Resistance to cyclophosphamide may occur due to decreased cellular penetration, increased competition from other nucleophilic substances, improved DNA repair or increased drug metabolism
True
Cyclophosphamide is FDA approved for treatment of mycosis fungoides
True
Cyclophosphamide can be used in the treatment of vasculitis
True
Cyclophosphamide is a useful agent in treating mucous membrane pemphigoid (cicatricial pemphigoid) particularly when there is involvement of the ocular mucosa
True
Cyclophosphamide is uncommonly used in the treatment of pemphigus
True (widespread availability of other less toxic medications I.e. Azathioprine and mycophenolate tempers the use of cyclophosphamide in immunobullous disease)
Cyclophosphamide is contraindicated in patients with a history of bladder cancer
True (genitourinary toxicity with haemorrhaging cystitis and bladder carcinoma is the single most widely recognised consequence of cyclophosphamide use)
Cyclophosphamide should be used with caution in patients with a history of lymphoproliferative disease
True (to be used with caution due to association of cyclophosphamide with non-Hodgkins B cell lymphoma and leukaemia)
Acrolein is the metabolite responsible for haemorrhagic cystitis, an adverse effect of cyclophosphamide
True (Mesna may be used as a scavenging thiol agent that binds acrolein in the bladder and reduce irritation)
Mesna (sodium 2-mercaptoethane sulfonate) may be used orally or intravenously as a protective measure against haemorrhagic cystitis from cyclophosphamide use, especially in high doses
True (though Mesna has also been associated with fixed drug eruption when used for this indication)
Bladder toxicity (haemorrhagic cystitis) is less frequent in patients on intravenous cyclophosphamide than oral form of the drug
True (perhaps due to the lower total dose used in the intravenous form as compared to oral form)
Increased fluid intake may prevent bladder toxicity (haemorrhagic cystitis) caused by cyclophosphamide
True
Mesna may be prescribed to patients on cyclophosphamide
True (co-administration of Mesna in dermatological doses of cyclophosphamide is not evidence based due to the lower doses prescribed in dermatological conditions, though Mesna can be considered for patients on prolonged courses of cyclophosphamide and/or high doses)
Continued monitoring of the urinary tract is indicated in all patients who have used cyclophosphamide
True (bladder cancer may arise decades after discontinuation of cyclophosphamide)
There is a potential association between cyclophosphamide and SCC
True (though much of this risk is found in transplant and oncology patients exposed to high doses for extended durations)
GI adverse effects affect 70-90% of cyclophosphamide users
True (this can be managed with ondansetron and dexamethasone)
Anaemia associated with cyclophosphamide and chlorambucil use is usually reversible
True (also less common)
Leukopenia is a dose-limiting common adverse effect from cyclophosphamide and chlorambucil
True
Thrombocytopenia usually occurs with higher doses of cyclophosphamide and chlorambucil
True
Pigmented band on the teeth is an irreversible adverse event from cyclophosphamide
True
Alopecia due to anagen effluvium is a reversible side effect of cyclophosphamide
True
Cyclophosphamide may cause hyperpigmentation of the skin and nails
True (just as in minocycline, hydroxychloroquine and hydroxyurea)
Amenorrhea may occur in 27-60% of women treated with cyclophosphamide
True (also in chlorambucil)
Premature ovarian failure from cyclophosphamide and chlorambucil may be prevented with luprolide acetate
True
Cyclophosphamide may cause azoospermia in men
True (testosterone may lessen this risk)
Urinalysis and cytological examination is indicated when the cumulative cyclophosphamide dose is > 50g
True
Evaluation for palpable lymphadenopathy and age appropriate cancer screening I.e. FOBT and Pap smear should be included in the follow up of patients on cyclophosphamide
True
Unlike cyclophosphamide (a prodrug), Chlorambucil is also metabolised in the liver but does not require activation in the liver (active drug)
True
Chlorambucil has a slower onset of action than cyclophosphamide
True (and also less toxic)
Unlike cyclophosphamide, metabolism of chlorambucil does not yield acrolein
True (and so chlorambucil does not cause haemorrhagic cystitis)
In dermatology, Chlorambucil is used most consistently in necrobiotic xanthogranuloma
True
Epilepsy and mood alterations are specific to chlorambucil
True (differs to cyclophosphamide)
There is a risk of carcinogenesis from chlorambucil use
True (as for cyclophosphamide, there is potential risk for leukaemia, non-Hodgkins lymphoma and SCC)
Hepatotoxicity is an uncommon adverse effect of chlorambucil
True
Drugs which may potentiate myelosuppressive, immunosuppressive and carcinogenic effects of cyclophosphamide and chlorambucil should be used with caution
True
There is possible decreased immunologic response with all vaccines and disseminated infection with live vaccines if used in Cyclophosphamide and chlorambucil patients
True
Cyclophosphamide and chlorambucil are teratogenic
True
