IC 9: Endocrine cancer Pharmacology Flashcards
What is the MOA of Tamoxifen?
o Competitively binds to estrogen receptors, blocking endogenous estrogen from binding to estrogen receptors (ER) in target tissues (e.g breast) -> tamoxifen-ER dimerises and translocates into the nucleus and binds to estrogen responsive element (ERE) -> estrogen responsive gene expression altered -> prevents cell activation and proliferation -> decreased cell survival
Note that it only blocks AF2 (1 of 2 transcription sites on the estrogen receptor) -> only a partial blocker
Which isomer of Tamoxifen is the one with anti-estrogenic effect?
Trans isomer
What are the characteristics of the metabolites of Tamoxifen?
They are active metabolites and have higher affinity for estrogen receptors than Tamoxifen
State the major pathway of Tamoxifen metabolisation and what is the metabolite formed, and how this pathway might be inhibited
N-demethylation (catalysed by CYP3A4)
N-desmethyl-tamoxifen formed
Inhibited by CYP3A4 inhibitors (e.g grapefruit and grapefruit juice)
State the minor pathway of Tamoxifen metabolism, metabolite formed and how this pathway may be inhibited.
4-Hydroxylation by CYP2D6
- Forms 4-hydroxytamoxifen
- Can be inhibited by Diphenhydramine (CYP2D6 inhibitor)
What is the most active metabolite of Tamoxifen and how is it formed?
4-hydroxy-N-desmethyltamoxifen (endoxifen) which is the most active metabolite of Tamoxifen
- CYP2D6 then CYP3A4 metabolism OR
- CYP3A4 then CYP2D6 metabolism
What are the side effects of Tamoxifen?
o Hot flashes
o ↑ risk of endometrial cancer ( result from cis-tamoxifen accumulation in uterus and exerting estrogenic effect)
o Venous thromboembolic events (DVT)
o Menstrual irregularities
o Vaginal bleeding and discharge (another sign that Tamoxifen may be starting to cause endometrial cancer)
o Nausea, vomiting
State special considerations of Tamoxifen if any
High doses could lead to acute neurotoxicity (tremor, hyperreflexia, unsteady gait, dizziness) -> no antidote for overdose, just give supportive treatment (e.g sit down, prevent falls)
What is the MOA of Pembrolizumab?
o Blocks PD-1 receptors on T-cells and prevents PD-L1 of cancer cells from binding to PD-1 and inactivating the T-cells
What are the ADRs of Pembrolizumab?
o Infusion related side effects (e.g rash, itch; may be sign of hypersensitivity)
o Fatigue
o Diarrhoea
o Nausea
o Joint pain
o (Life threatening) Immune-related inflammation
What are the contraindications of Pembrolizumab?
o If a patient is taking corticosteroids or immunosuppressants (To be stopped before starting pembrolizumab. Can add back after starting Pembrolizumab)
o Not to be administered to pregnant women (may increase risk of miscarriage)
o Patients who have a history of severe reaction (eg. hypersensitivity) to another antibody therapy, other illnesses (eg.infection, liver/kidney diseases etc) -> consult doctors.
How is Pembrolizumab metabolised?
Cleared through non-specific catabolism into small peptides and amino acids through general protein degradation routes
What may affect the clearance of Pembrolizumab?
- Albumin and bilirubin levels (affect degree of protein binding)
- Type of cancer
- Gender (females have lower clearance -> may need dose adjustment)
What is the MOA of Leuprorelin?
o Binds to GnRH receptors in anterior pituitary and initially stimulate release of FSH and LH -> over time, continuous stimulation of GnRH receptors lead to desensitisation and downregulation of GnRH receptors -> decreased FSH and LH release -> decreased Testosterone production -> cancer cells cannot grow and undergo apoptosis.
How is Leuprorelin metabolised?
Degraded proteolytically (potentially by peptidases) into inactive peptides
NOT metabolised by liver CYP450
