190: Cytotoxic and Antimetabolic Agents Flashcards
What are the primary uses of Methotrexate (MTX) in dermatology?
Methotrexate (MTX) is primarily used to treat severe psoriasis, psoriatic arthritis, dermatomyositis, and various cutaneous diseases.
What is the mechanism of action of Methotrexate (MTX)?
Methotrexate (MTX) acts by inhibiting dihydrofolate reductase, partially inhibiting thymidylate synthase, and inhibiting DNA methylation.
What are the pharmacokinetics of Methotrexate (MTX)?
The pharmacokinetics of Methotrexate (MTX) include rapid absorption through the GI tract, approximately 67% bioavailability in adults, peak plasma levels occurring 1 to 3 hours after administration, a half-life of 4 to 5 hours, and elimination primarily through the kidneys.
How does methotrexate cause immunosuppression?
Methotrexate inhibits dihydrofolate reductase, reducing folic acid metabolism, which decreases the availability of purine nucleotides and thymidylate, leading to immunosuppression.
What is the typical dosing regimen for Methotrexate (MTX) in treating dermatological conditions?
The typical regimen includes a single weekly dose of MTX or an older regimen of a weekly dose divided into 3 equal parts. Doses vary based on condition, with less than 30 mg/week for dermatology.
What are the absolute contraindications for the use of Methotrexate (MTX)?
The absolute contraindications include pregnancy, lactation, and bone marrow suppression.
What is the recommended monitoring protocol for patients on Methotrexate therapy?
The recommended monitoring protocol includes initial testing with a 2.5 to 5 mg test dose, repeat laboratory studies 1 week later, ongoing evaluation every 1 to 2 months, and liver function testing not performed earlier than 5 days after dosing.
How does the response to low-dose Methotrexate in patients with mycosis fungoides vary?
The response can range from definite improvement to an overall response in erythrodermic and plaque mycosis fungoides, with a median dose of 25 mg/week.
What are the key contraindications for initiating methotrexate therapy?
Key contraindications include pregnancy, lactation, significant anemia, leukopenia, thrombocytopenia, and active infections.
What are the recommended actions for patients with grade IIIA histology when using Methotrexate (MTX)?
Patients with grade IIIA histology may continue MTX but should undergo a repeat liver biopsy in 6 months.
What non-invasive alternatives to liver biopsy are suggested for monitoring liver fibrosis in patients on MTX?
Non-invasive serum biomarkers such as procollagen (PIIINP) and FibroTest/FibroSURE, along with ultrasound, are suggested.
What is the most important acute adverse effect of Methotrexate (MTX)?
The most important acute adverse effect is myelosuppression, which can lead to neutropenia and life-threatening bone marrow toxicity.
What are the risk factors for bone marrow toxicity in patients receiving Methotrexate?
Risk factors include advanced age, poor renal function, hypoalbuminemia, lack of folate supplementation, and concurrent administration of conflicting medications.
What should be done if liver transaminases exceed 2- to 3-fold normal values in patients taking Methotrexate?
A dose reduction of Methotrexate is indicated.
What is the recommended action if liver transaminases exceed 5-fold normal values in patients on Methotrexate?
It is recommended to discontinue Methotrexate and withhold it for 1 to 2 weeks before repeating liver function tests.
What are the potential pulmonary effects associated with Methotrexate use?
Potential pulmonary effects include acute pneumonitis and pulmonary fibrosis, which can be sudden and severe.
What is the significance of folate supplementation in patients taking Methotrexate?
Folate supplementation reduces gastrointestinal symptoms and adverse effects without compromising the efficacy of Methotrexate.
What is the recommended timing for administering folinic acid (leucovorin) after Methotrexate dosing?
Folinic acid should be given at least 24 hours after the dose of weekly Methotrexate.
What are the signs of Methotrexate overdose and the recommended treatment?
Signs may include severe toxicity symptoms. The recommended treatment is prompt administration of folinic acid (leucovorin) within 24-36 hours after overdose.
What are the key risk factors for methotrexate-induced bone marrow toxicity?
Risk factors include advanced age, poor renal function, hypoalbuminemia, lack of folate supplementation, and concurrent administration of conflicting medications.
A patient on methotrexate presents with oral ulcers and skin ulcerations on the lower legs. What should be the immediate course of action?
Laboratory studies should be conducted, and methotrexate dosage should be reduced or discontinued.
A patient on methotrexate develops elevated liver transaminases. What should be the next steps?
If transaminases exceed 2-3 times the normal values, dose reduction is indicated. If they exceed 5 times, methotrexate should be discontinued.
What are the common complications of methotrexate-induced pulmonary toxicity?
Complications include acute pneumonitis and pulmonary fibrosis, with symptoms including new onset of cough and shortness of breath.
A patient on methotrexate develops severe nausea and vomiting. What are the management options?
Management includes folate supplementation, antiemetics, and possibly switching to subcutaneous administration.
What is the mechanism of action of hydroxyurea in cancer treatment?
Hydroxyurea impairs DNA synthesis by inhibiting ribonucleotide diphosphate reductase, reducing nucleotides to deoxynucleotides.
What are the recommended monitoring guidelines for patients on hydroxyurea?
CBC with differential should be repeated weekly during the first month, then monthly. Liver function studies should be monitored monthly until stable.
What are the indications for using hydroxyurea in dermatology?
Hydroxyurea is chiefly used for the treatment of psoriasis, including plaque, pustular, and erythrodermic forms.
What are the pharmacokinetics of hydroxyurea?
Hydroxyurea is well absorbed after oral administration, with serum levels peaking within 2 hours.
What is the mechanism of action of hydroxyurea in treating psoriasis?
Hydroxyurea impairs DNA synthesis by inhibiting ribonucleotide diphosphate reductase.
What are the key monitoring parameters for patients on hydroxyurea?
Monitoring includes weekly CBC with differential during the first month, transitioning to monthly if stable.
What is the role of folinic acid in methotrexate overdose?
Folinic acid provides an alternative supply of DNA and RNA precursors, bypassing the need for dihydrofolate reductase.
What are the common complications associated with hydroxyurea use?
Common complications include myelosuppression, transient hepatitis, and cutaneous side effects.
How does azathioprine’s bioavailability compare to 6-mercaptopurine (6-MP)?
Azathioprine has improved bioavailability, with 88% of the oral dose being absorbed through the GI tract.
A patient on hydroxyurea develops ulcers over pressure points. What is the likely cause, and how should it be addressed?
The ulcers are a cutaneous side effect of hydroxyurea. The drug should be discontinued.
What is the mechanism of action of azathioprine in immunosuppression?
Azathioprine is metabolized to 6-mercaptopurine, which inhibits RNA and DNA synthesis.
A patient on hydroxyurea develops serpentine supravenous hyperpigmentation. What is the likely cause, and how should it be managed?
The hyperpigmentation is a cutaneous side effect of hydroxyurea. The drug should be discontinued.
What is the recommended starting dose of azathioprine for pediatric patients with atopic dermatitis based on TPMT levels?
The recommended starting dose is 2.0 to 2.5 mg/kg.
What are the common side effects associated with azathioprine use?
Common side effects include myelosuppression, thrombocytopenia, GI effects, and hepatic effects.
What precautions should be taken when initiating therapy with azathioprine?
Precautions include baseline laboratory tests and monitoring for infections.
What is the significance of TPMT levels in azathioprine therapy?
Dosing should be based on the patient’s TPMT expression to minimize toxicity.
What laboratory tests are recommended for azathioprine therapy?
CBC with differential, renal and liver function testing, and erythrocyte TPMT activity assay.
What should be considered in high-risk populations for mycobacterial infections?
Tuberculin skin testing or QuantiFERON gold should be considered.
How should patients be monitored for infections during azathioprine treatment?
Patients should be monitored for herpes virus infections and other infections.
Why are TPMT levels significant in azathioprine therapy?
Dosing should be based on the patient’s TPMT expression to minimize the risk of toxicity. Acute severe neutropenia is a major concern, occurring in 86% of patients receiving standard dosing, particularly in those with low TPMT activity. TPMT levels should be repeated in cases of nonresponse or change in response to therapy.
What are the risks associated with azathioprine therapy?
Risks include acute severe neutropenia, increased toxicity in older adults and those with impaired renal or hepatic function, myelosuppression, and infections.
What should be done if a patient on azathioprine develops severe neutropenia?
The drug should be discontinued, and TPMT levels should be reassessed.
What are the common gastrointestinal side effects of azathioprine?
Common side effects include nausea, vomiting, and diarrhea. Management includes gradual dose escalation, administration with food, splitting the daily dose, or using antiemetics.
What are the key monitoring parameters for patients on azathioprine?
Monitoring includes biweekly CBC with differential for the first 2 months, monthly for the next 2 months, and every 2 months thereafter. Liver function tests should be conducted monthly for 3 months, then bimonthly.
What is the role of TPMT testing in azathioprine therapy?
TPMT testing helps guide dosing and reduces the risk of myelosuppression by identifying patients with low TPMT activity.
What are the potential adverse effects associated with azathioprine use?
Adverse effects include hepatic venoocclusive disease, associated pancreatitis, anaphylaxis, increased risk for skin cancer and lymphoma, and drug fever.
What is the recommended monitoring protocol for patients on thioguanine?
Baseline laboratory studies: CBC with differential, liver function studies, and TPMT activity assay. Weekly blood counts and liver function tests initially, transitioning to biweekly monitoring as the dose stabilizes.
What is the mechanism of action of thioguanine?
Thioguanine inhibits purine synthesis, produces nucleotide analogs that induce cytotoxic activity through incorporation into cellular DNA, and induces apoptosis preferentially against activated T lymphocytes.
What are the indications for thioguanine in clinical practice?
Indicated for treatment of psoriasis, lupus, and atopic dermatitis.
What are the dosing guidelines for thioguanine?
Start with 80 mg twice weekly, advancing by 20 mg every 2 to 4 weeks, up to a maximum of 160 mg 3 times weekly.
What is the cause of multiple squamous cell carcinomas in a patient on azathioprine?
Azathioprine increases UVA radiation absorption, leading to mutagenic DNA damage. Mitigation includes sun avoidance and broad-spectrum sunscreen.
What are the common adverse effects associated with thioguanine treatment for psoriasis?
Common adverse effects include myelosuppression and GI disturbances such as nausea and diarrhea.
How does cyclophosphamide function as a cytotoxic agent?
Cyclophosphamide is an alkylating agent that acts primarily by crosslinking DNA, leading to cell death.
What is the pharmacokinetic profile of cyclophosphamide?
Bioavailability of 74%, peak plasma levels within 1 hour, half-life ranges from 2 to 10 hours.
What are the indications for using cyclophosphamide in dermatology?
Used as a steroid-sparing agent in serious diseases such as pemphigus vulgaris and mucous membrane pemphigoid.
What is the mechanism of action of tacrolimus?
Tacrolimus inhibits calcineurin by binding to FK506 binding protein, leading to decreased activation and proliferation of T lymphocytes.
What are the hematologic effects of thioguanine?
Common effects include myelosuppression, with thrombocytopenia often being the earliest indicator.
What are the common side effects of thalidomide in dermatologic use?
Side effects include teratogenic effects, peripheral neuropathy, sedation, and thromboembolic events.
What is the mechanism of action of mycophenolate mofetil (MMF)?
MMF suppresses T lymphocyte function by inhibiting intracellular calcineurin.
What is the recommended hydration protocol for patients undergoing cyclophosphamide therapy?
Vigorous hydration should begin 24 hours before therapy and continue throughout the treatment.
What are the contraindications for initiating cyclophosphamide therapy?
Contraindicated in patients with a history of transitional cell carcinoma of the bladder and in pregnant or lactating patients.
What baseline laboratory evaluations are necessary before starting cyclophosphamide therapy?
CBC with differential, serum chemistry profile, liver function testing, and urinalysis.
What is the significance of monitoring blood counts and urinalysis during cyclophosphamide therapy?
To detect abnormalities such as red blood cells in urine or changes in white blood cell counts.
What are the common gastrointestinal side effects associated with cyclophosphamide use?
Nausea and vomiting are the most common GI side effects.
What is the risk of bladder toxicity associated with cyclophosphamide?
Bladder toxicity can be mitigated by ensuring vigorous hydration and using mesna.
What is the increased risk of cancer associated with cyclophosphamide therapy?
Increased risk of various solid organ tumors, including non-Hodgkin lymphoma and leukemia.
What prophylactic measures should be considered for patients on cyclophosphamide therapy?
Prophylaxis may include treatments like trimethoprim-sulfamethoxazole or aerosolized pentamidine.
What is the recommended prophylactic treatment for Pneumocystis jirovecii pneumonia in patients on cyclophosphamide?
Prophylactic options include trimethoprim-sulfamethoxazole, aerosolized pentamidine, oral dapsone, or oral atovaquone.
What are the key contraindications for initiating cyclophosphamide therapy?
Contraindications include a history of transitional cell carcinoma of the bladder and pregnancy.
What is the role of mesna in cyclophosphamide therapy?
Mesna binds to the metabolite acrolein in the bladder, reducing the incidence of hemorrhagic cystitis.
What is the likely cause of diffuse brown hyperpigmentation of the skin in a patient on cyclophosphamide?
The hyperpigmentation is a cutaneous side effect of cyclophosphamide, usually resolving within 6-12 months after discontinuation.
What are the indications for using chlorambucil in dermatology?
Indicated as a steroid-sparing agent in conditions such as pemphigus vulgaris and bullous pemphigoid.
What are the common side effects associated with chlorambucil?
Common side effects include nausea, vomiting, azoospermia, amenorrhea, and pulmonary fibrosis.
What is the mechanism of action of chlorambucil?
Chlorambucil works by crosslinking DNA, disrupting DNA replication and transcription.
What are the pharmacokinetics of chlorambucil?
Well absorbed with 87% bioavailability, 99% protein bound, half-life approximately 1.5 hours.
What are the key safety guidelines for patients on chlorambucil?
Regular CBC monitoring, liver function tests, urinalysis, and cancer screening are essential.
What are the key risk factors for cyclophosphamide-induced gonadal failure?
Risk factors include age and cumulative dose.
What are the primary indications for Pegylated Liposomal Doxorubicin (PLD)?
Primarily indicated for AIDS-related Kaposi sarcoma and cutaneous T-cell lymphoma.
What is the mechanism of action of anthracyclines like doxorubicin?
Anthracyclines intercalate within DNA and RNA, disrupting synthesis and leading to cell death.
What are the common side effects associated with Pegylated Liposomal Doxorubicin (PLD)?
Common side effects include myelosuppression, nausea, neutropenia, and hepatotoxicity.
What precautions should be taken before initiating therapy with Pegylated Liposomal Doxorubicin (PLD)?
Conduct a thorough history and physical examination, assess for prior use of anthracyclines, and perform baseline laboratory studies.
What is the recommended dosing regimen for Pegylated Liposomal Doxorubicin (PLD)?
Administered at a dose of 20 to 30 mg/m² infused intravenously over 30 to 60 minutes once every 2 to 3 weeks.
What are the common cutaneous side effects of doxorubicin?
Common side effects include hyperpigmentation of the skin and nails, alopecia, and acral erythema.
What is the mechanism of action of pegylated liposomal doxorubicin (PLD)?
PLD intercalates within DNA and RNA, causing defective synthesis and cell death.
What are the common adverse effects of pegylated liposomal doxorubicin (PLD)?
Adverse effects include myelosuppression, hepatotoxicity, nausea, and alopecia.
What is the mechanism of action of pegylated liposomal doxorubicin (PLD)?
PLD intercalates within DNA and RNA, causing defective synthesis and cell death. Its liposomal formulation improves tolerance and tumor penetrance.
What are the common adverse effects of pegylated liposomal doxorubicin (PLD)?
Adverse effects include myelosuppression, hepatotoxicity, nausea, vomiting, alopecia, acral erythema, and radiation recall reactions.
What are the common nail complications associated with cytotoxic agents?
Common nail complications include malformed nail plates (dystrophy), Beau lines, onycholysis or onychomadesis, nail bed pain, splinter hemorrhage, and nail pigmentation.
What is Neutrophilic Eccrine Hidradenitis (NEH) and its association with cytotoxic agents?
NEH is characterized by tender, erythematous macules, papules, and plaques on the trunk, neck, and extremities. It develops after exposure to cytotoxic agents and resolves spontaneously.
What is acral erythema and its clinical significance in chemotherapy?
Acral erythema is a cutaneous reaction that occurs after chemotherapy characterized by painful, sharply demarcated erythema of the palmoplantar surfaces with associated edema.
What is the likely condition for a patient with painful, sharply demarcated erythema on the palms and soles during chemotherapy?
The patient likely has toxic acral erythema, common with agents like cytarabine, doxorubicin, fluorouracil, and methotrexate. Management includes analgesics and emollients.
What unique skin reaction can long-term hydroxyurea therapy produce?
Long-term hydroxyurea therapy may produce a unique form of acral erythema that resembles dermatomyositis, without any corresponding muscle findings.
What is the most common cause of inflamed actinic keratoses in chemotherapy?
Systemic fluorouracil is the most common cause of inflamed actinic keratoses, usually developing within 1 week of initiating chemotherapy.
What type of hyperpigmentation can Bleomycin cause?
Bleomycin may produce a unique form of flagellate (linear) hyperpigmentation of the skin, typically after cumulative doses of 90 to 285 mg.
How do phototoxic reactions differ from photoallergic reactions in chemotherapy?
Phototoxic reactions begin rapidly after administration and mimic sunburns, while photoallergic reactions present as an eczema-like process and may be delayed.
What is a common complication of extravasation of chemotherapy agents?
A common complication is tissue necrosis, which can be devastating. Immediate treatment includes discontinuing the infusion and applying hot or cold packs.
What is the significance of radiation recall reactions in chemotherapy?
Radiation recall reactions consist of erythema confined to an area of prior radiation exposure, which may develop vesiculation in severe cases.
What should be done for a patient on methotrexate experiencing a recall reaction to a prior sunburn?
Management includes avoiding further sun exposure and symptomatic treatment.
What are the common complications of chemotherapy-induced photosensitivity?
Complications include phototoxic reactions resembling sunburns and photoallergic reactions presenting as eczematous processes.
What are the histologic findings associated with extravasation injuries from cytotoxic agents?
Extravasion injuries have demonstrated surprisingly few inflammatory cells in areas of tissue damage.
What are the characteristics of sclerotic dermal reactions caused by bleomycin and docetaxel?
Sclerotic dermal reactions may be localized, regional, or diffuse and can mimic morphea or systemic sclerosis.
What is the Raynaud phenomenon and its association with cytotoxic agents?
Raynaud phenomenon can occur with or without digital ulceration, often associated with bleomycin, vincristine, cisplatin, or gemcitabine.
What are the common oral complications associated with chemotherapy?
Oral complications may occur in up to 40% of patients, with symptoms including burning and mucosal erythema, painful erosions, and ulcerations.
How can mucositis induced by cytotoxic agents be managed?
Management includes maintaining oral hygiene, using antibiotics and antifungal agents, and employing simple modalities like ice chips for symptomatic relief.
What is mucosal hyperpigmentation and how does it manifest in patients receiving cytotoxic agents?
Mucosal hyperpigmentation may manifest as linear, patchy, or macular patterns, often affecting areas like the gingival margin or tongue.
What is the likely cause of mucosal hyperpigmentation in a patient on methotrexate?
Mucosal hyperpigmentation is a side effect of methotrexate and usually resolves slowly over weeks to months after discontinuation.
