IC9: Pharmacology of selected drugs for endocrine cancers Flashcards
What is Tamoxifen indicated for?
Breast cancer
What is the MOA of Tamoxifen?
- Selective estrogen receptor modulator (SERM)
- It competitively blocks endogenous estrogen binding to the ER in the target tissue. The tamoxifen-ER complex alters estrogen-responsive gene expression, thus preventing cell activation and proliferation
- Has anti-estrogenic and estrogenic effects
- Has tissue-specific effects
Why does Tamoxifen have both estrogenic and anti-estrogenic effects?
Tamoxifen exists in cis- and trans- stereoisomers. The cis-isomer has estrogenic activity while the trans-isomer has anti-estrogenic activity
What is the metabolism pathway of Tamoxifen?
- Phase 1: Hydroxylation, N-oxidation, dealkylation
- Phase 2: glucuronidation, sulfation
- Major pathway of metabolism: N-demethylation (catalysed by CYP3A4)
- One of the major metabolites: N-desmethyltamoxifen
- Has active metabolites by CYP2D6: 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) are minor metabolites that exhibit affinity for the estrogen receptor that is greater than that of tamoxifen
Are there any drug or food interactions with Tamoxifen?
- Grape fruit (juice) inhibits CYP3A4
- Diphenhydramine can inhibit CYP2D6
6
What are the side effects of Tamoxifen?
- Hot flashes
- Increased risk of endometrial cancer
- Venous thromboembolic events (DVT)
- Menstrual irregularities
- Vaginal bleeding and discharge
- Nausea, vomiting
Toxicity of Tamoxifen
High doses could lead to acute neurotoxicity (tremor, hyperflexia, unsteady gait, dizziness)
What is Pembrolizumab indicated for?
Cervical cancer
MOA of Pembrolizumab
- Cancer cells produce a particular protein called PD-L1 that interacts with PD-1, which is important for immune cells to recognise cancer cells. The cancer cell creates ligand interaction to fool the immune cell, preventing it from triggering its immune response
- Pembrolizumab is a PD-1 blocker, which binds to PD-1, releasing PD-1 pathway-mediated inhibition of T-cell activities
6
Side effects of Pembrolizumab
- Infusion-related side effects like rash and itchiness
- Nausea
- Diarrhoea
- Fatigue
- Joint pain
- (Life-threatening) immune-related inflammation on lung, endocrine organs, kidney, liver, sepsis
Contraindications of Pembrolizumab
- Patient taking corticosteroids or immunosuppressants (stop before starting Pembrolizumab)
- Pregnant women (increases risk of miscarriage)
- Patients who have a history of severe reaction to another antibody therapy, other illnesses (consult doctor)
What is Leuprorelin indicated for?
Prostate cancer
MOA of Leuprorelin
- Synthetic GnRH analogue acting as an agonist at pituitary GnRH receptors
- Decreased androgen (testosterone) production in testes, minimising the stimulatory effect on androgen-sensitive cancer cell, causing cancer cell to undergo apoptosis
- Continuous administration inhibits FSH and LH release, suppressing androgen synthesis
Side effects of Leuprorelin
- Local pain at injection site
- Hyperglycemia
- Hyperlipidemia
- GI disturbances
- Altered mood
- Headaches/migraines
- Flushes
- Loss of libido, impotence
Contraindications of Leuprorelin
- Hypersensitivities to Leuprorelin or other GnRH agonists
- Pre-existing heart disease
- Patients at risk of osteoporosis e.g. elderly
What is the indication of Bicalutamide?
Prostate cancer
Can Bicalutamide be used as monotherapy?
No, it should be prescribed together with Leuprorelin for prostate cancer. This is because it blocks AR, causing increased LH secretion and thus higher serum testosterone levels
MOA of Bicalutamide
- Anti-androgen
- Acts competitively to antagonise androgen receptor
- Inhibits nuclear translocation of the AR and interaction of the AR with the promoter at the AR response element. The inhibition of AR-dependent transcription impairs cell proliferation and triggers apoptosis in cancer cells
- Prostate growth depends on androgens, so androgen deprivation decreases progression of prostate cancer
Metabolism of Bicalutamide
- Stereoselective
- S-bicalutamide [inactive]: glucuronidation
- R-bicalutamide [active]: hydroxylation (CYP3A4), followed by glucuronidation
5
Side effects of Bicalutamide
- Gynecomastia
- Sexual dysfunction
- Fatigue
- GI disturbance
- Seizure (rare)
