Antimetabolites Flashcards
What is the MOA of methotrexate?
Folate antagonist/blocks cell division
- inhibits dihydrofolate reductase
- inhibits thymidylate synthetase
Anti-inflammatory (adenosine)
Has effects on T cells and keratinocytes
What are the contraindications to methotrexate?
Hypersensitivity
Pregnancy/lactation
Severe hepatic or renal disease
EtOH abuse
Active/recent infection or malignancy
Cytopaenias
Unreliable patient
What are the drug interactions of methotrexate?
- Other folate inhibitors eg TMP, dapsone, sulfonamides
- Renal: NSAIDs, phenytoin, tetracyclines
- Hepatotoxicity: EtOH, retinoids
What are the contraception requirements for methotrexate?
Females: negative pregnancy test within 1 week of starting, off the medication for at least 1 month before conceiving
Males: no requirements
What are the adverse effects of methotrexate?
GI effects
Mucositis/stomatitis
Alopecia
Photosensitivity/toxicity
Malaise, fatigue
Haem: Cytopaenias
Resp: pneumonitis/fibrosis
Infection & malignancy
Abortifacient
What is the baseline and ongoing monitoring requirement for methotrexate?
Baseline
Complete Hx & exam to exclude infection and malignancy
FBC, UEC, LFT, BhCG, BSL, lipids
Immunosuppression screen
Fibroscan
Vaccination catch up
Ongoing
BMI/waist circumference every 6 months
FBC, UEC, LFT every 2 weeks for 2 months and then every 3 months
BSL, lipids every 6 months
Fibroscan every 1-3 years
What are the contraindications of azathioprine?
Hypersensitivity
Pregnancy/lactation
TMPT deficiency
Severe hepatic or renal impairment
Active/recent infection or malignancy
Prior use of alkylating agent
Unreliable patient
What are the drug interactions of azathiprine?
- Allopurinol, febuxostat (XO inhibitors)
- Methotrexate (incr. 6-MP)
- ACE inhibitors (incr. risk of leukopenia)
- Other immunosuppressants
What are the adverse effects of azathioprine?
GI effects, transaminitis, pancreatitis
Cytopaenias
Increased risk of infection & malignancy
Hypersensitivity syndrome
Teratogenicity
What is the MOA of azathioprine?
Purine analogue
Affects numbers / function of
- T cells
- B cells
- antigen-presenting cells
What are the 3 pathways of metabolism for azathioprine?
- TPMT (inactive)
- Xanthine oxidase (inactive)
- HGPRT (active)
How is azathioprine dosed based on TPMT levels?
- Normal 2-2.5mg/kg
- Heterozygous 1-1.5mg/kg
- Homozygous - Do NOT use
What baseline and ongoing monitoring is required for azathioprine?
Baseline
Complete Hx & exam incl. skin & LNs
TPMT level
FBC, UEC, LFT, BhCG,
Immunosuppression screen
Age appropriate malignancy screen
Contraception
Consider PJP prophylaxis
Monitoring
FBC, LFT every 2 weeks for 2 months and then every 3 months
* more frequent if increase in dose or hepatic or renal disease
FSE & LN every 6 months
What are the contraindications to mycophenolate?
Hypersensitivity
Pregnancy/lactation
Gastritis/PUD/GI bleed
Severe hepatic, renal or cardiopul dz
Unreliable patient
What is the MOA of mycophenolate?
Inhibits inosine monophosphate dehydrogenase (enzyme involved in purine metabolism)
Cytotoxic to lymphocytes made by “de novo” pathway
What are the adverse effects of mycophenolate?
GI effects
Gastritis/PUD/GI bleed
GU: urgency, frequency, dysuria
CNS: headache, tinnitus, weakness
Cytopaenias
Infection & Malignancy
Teratogenic
What are the drug interactions of mycophenolate?
Reduces MMF: PPI, antacids, iron
Increased MMF: probenecid, aciclovir
Reduced enterohepatic recirculation: cholestyramine
Other immunosuppressants
What baseline and ongoing monitoring is required for mycophenolate?
Baseline
Complete Hx and exam
FBC, UEC, LFT, BhCG
Immunosuppression screen
Vaccinations catch up
Age appropriate malignancy screen
Contraception for 1 month prior and 6 months post
Monitoring
*FBC, UEC, LFT every 2 weeks for 1 month and then every 3 months
What is the MOA of cyclosporin?
- Inhibits IL-2 production —> reduced T cell proliferation
- Reduced activity of NFAT1 —> inhibits T cell proliferation
- Inhibits IFN-gamma production —> reduced keratinocyte proliferation
- Binds to HSP 56 —> reduced pro inflammatory cytokines eg IL-1, TNF alpha
What are the drug interactions for cyclosporin?
- CYP3A4 substrates/inducers/inhibitors
- Renotoxics: NSAIDs, aminoglycosides, diuretics
- Spironolactone (Hyperkalemia)
- Lovastatin (Myopathy)
- Other immunosuppressants
What are the adverse effects of cyclosporin?
- Renal dysfunction
- Hypertension
- Hypercholesterolemia
- Hyperkalemia
- Hyperuricemia
- GI effects
- Gingival hyperplasia, hypertrichosis
- Other: headache, parenthesia, tremor, myalgia/arthralgia
- Infection
- Malignancy (NMSC, lymphoma)
What baseline and ongoing monitoring is required for cyclosporin?
Baseline
Complete Hx & exam (rule out infection and malignancy)
Blood pressure (2 separate occasions)
FBC, UEC, CMP, LFT, urate, lipids, BhCG
Immunosuppression screen
Vaccinations catch up
Age appropriate malignancy screening
Ongoing
Weekly: Blood pressure
Fortnightly: UEC, Urinalysis
Monthly: FBC, CMP, LFT, urate, lipids
6 monthly: skin exam incl. LNs
How is dosing of cyclosporine affected by renal impairment?
Cyclosporine is contraindicated in renal disease
What are MEK inhibitors used for in dermatology?
BRAF +ve malignant melanoma
What are the contraindications to MEK inhibitors?
Hypersensitivity
Pregnancy/lactation
Children <18 years
Severe cardiac/hepatic/renal disease
What are the adverse effects of MEK inhibitors?
Acne, xerosis, itch, rash, stomatitis, paronychia
GI effects
Hypertension, cardiomyopathy
ILD
VTE
Lymphoedema
Retinal detachment
What baseline and ongoing monitoring is required for MEK inhibitors?
Full hx and exam inc. skin
FBC, UEC, LFT, urinalysis, BhCG, ECG
What is the rate of hypertension in patients treated with cyclosporin?
20-55%
When does hypertension develop in patients treated with cyclosporine?
First few weeks
True or false,
Nephrotoxicity arising from cyclosporine use is usually reversible
True
