endocrine cancer Flashcards
1
Q
what are the meds used for endocrine cancer?
A
- Tamoxifen
- Pembrolizumab
- Leuprorelin
- Bicalutamide
just rmb: tplb: tammy’s pen leaks bicarbonate
2
Q
which meds are small molecules? which are big molecules?
A
small: Tamoxifen
big: Pembrolizumab
3
Q
what are the indications for the following drugs?
A
- Tamoxifen: breast cancer
- Pembrolizumab: cervical cancer
- Leuprorelin: prostate cancer
- Bicalutamide: prostate cancer
4
Q
what are the features of tamoxifen?
A
- Belongs to a class called Selective Estrogen Receptor Modulator (SERM)
- Targets estrogen receptor
- Cancer has many targets: DNA, RNA, Receptors, Enzymes, Microtubules
- 4 Tablet preparations
- Strengths: 10mg, 20mg
5
Q
how does tamoxifen for breast cancer work?
A
- Competes with endogenous estrogen to bind to estrogen receptor on tumour cell in target tissue (eg. breast) —> Tamoxifen-ER complex alters estrogen-responsive gene expression by dissociating aF2 domain required for transcription and translation —> Prevents tumour cell activation and proliferation
- Subsequently enters nucleus to bind to DNA —> Suppress cell division and proliferation, proteins and signals
6
Q
what effects does tamoxifen for breast cancer provide? what is the structure?
A
- Exhibits estrogenic + anti-estrogenic effects
- Exhibits tissue-specific effects
7
Q
how does tamoxifen for breast cancer exhibit estrogenic + anti-estrogenic effects?
A
- Stereoisomeric structure: Exists in different forms that are mirror images of each other (enantiomers- trans and cis stereoisomers) but cannot be superimposed
- Cis-isomer: Estrogenic activity —> Promote growth of estrogen-dependent breast cancer cells
- Trans-isomer: Anti-estrogenic activity —> Commonly used form for treating breast cancer
7
Q
how does tamoxifen for breast cancer Exhibits tissue-specific effects?
A
Depends on apparent volume of distribution
8
Q
what is the pkpd (absorption) for tamoxifen for breast cancer?
A
- Absorption
- 100% bioavailability —> Given orally as tablets
- Reaches peak conc after 5h of administration
- Steady state up to 16 weeks
9
Q
what is the pkpd (distribution) for tamoxifen for breast cancer?
A
- Highly plasma protein bound (albumin)
- Apparent volume of 50-60L/kg —> Average weight is 60kg so 3000-3600L which is alot
- Tend to concentrate or move out into specific tissues: Breast, uterus, ovary (and liver, kidney, lung, pancreas) —> Exert anti-estrogenic and thus anti-cancer effect
- As compared to plasma conc, Uterus conc is x2-3 times higher and Breast conc is 10 fold higher
10
Q
what is the pkpd (metabolism) for tamoxifen for breast cancer?
A
- Type of metabolites depend on interaction of CYP450
- First metabolite
- CYP3A4: N-desmethyl-tamoxifen
- Major pathway: N-demethylation
- t1/2 = 14 days: Takes a while to reach steady state as conversion to endoxifen, depends on CYP450 metabolism in the liver
- CYP2D6: 4-OH tamoxifen (have some anti-cancer property)
- CYP3A4: N-desmethyl-tamoxifen
- Second metabolite
- Endoxifen (most active tamoxifen)
- First metabolite
11
Q
what is the pkpd (excretion) for tamoxifen for breast cancer?
A
Not alot in urine since liver metabolism
12
Q
if take tamoxifen for breast cancer, what should the pt avoid?
A
Avoid!!
Pomelo, Grape fruit and its juice inhibit CYP3A4
Diphenhydramine (in cough and cold meds) inhibit CYP2D6
13
Q
what other indications does tamoxifen have?
A
- Breast cancer (early and metastatic (cancer has spread))
- Pre and post menopausal women
- Chemoprevention of breast cancer in women at high risk
- Reduces severity of osteroporosis (side benefit as there are better drugs for this)
14
Q
what are the side effects of taking tamoxifen for breast cancer?
A
- Hot flashes: Face, neck, chest feeling warm
- Increase risk of endometrial cancer
- Deep vein thrombosis (DVT): Blood clot (thrombus) forms in deep veins, usually legs
- Irregular menses
- Vaginal bleeding, discharge
- N/v
15
Q
what toxicity is associated with tamoxifen for breast cancer?
A
If dose is too high —> Acute neurotoxicity —> Tremor, unsteady movement, dizziness —> So give symptomatic support as no treatment
16
Q
is tamoxifen taken by body builders?
A
- Tamoxifen inhibits estrogen receptor
- Guys take alot of androgenic substances —> Androgens broken down into estrogen
- To prevent estrogen generated creating male gynecomastia (development of breast) —> Tamoxifen taken to block estrogen effect to develop male breast LOL knn while suffering tamoxifen side effects/ toxicity
17
Q
what is prembrolizumab?
A
Biologic (big molecule), Antibody (-mab);
used for Cervical cancer
18
Q
what features does pembrolizumab for cervical cancer have?
A
- Fusion of human version and mouse version to inhibit cancer metastasis
- Chimera: Mouse version has very high affinity towards PD-1 receptors
- Recombinantly manufactured from CHO cells
note: Chimera: Genetically engineered molecule by combining two different species to enhance certain properties or functions
19
Q
how does pembrolizumab for cervical cancer work?
A
- Immune Checkpoint Inhibitor
- Binds to PD-1 to block interaction between the programmed cell death protein-1 (PD-1) receptor on T cells and its ligands, PD-L1 and PD-L2, expressed on surface of cancer cells —> inhibits the inhibition of T cell activation (basically enables further T cell activation) —> Allow continuation of attacking of cancer cells
20
Q
whats the pkpa for pembrolizumab for cervical cancer?
A
- Administration
- IV Infusion over 30 mins (slow infusion)
- Adult dosage: 200mg, Q3 weeks (may last for >8months)
- Distribution
- Small apparent volume of distribution ~7L (around circulatory volume) —> so limited to blood circulation and does not really get out to extravascular circulation
- Metabolism
- Biologics made of protein
- Non-specific catabolism by proteases into amino acids
- t1/2 (stay in body): 27 days
- Reach steady state after ~19 weeks
- Elimination
- Clearance determined by type of cancer and gender
- Females have lower clearance
- Clearance determined by type of cancer and gender
21
Q
whats the side effects for pembrolizumab for cervical cancer?
A
- Infusion-related side effects due to hypersensitivity: Rash, itchiness
- Fatigue
- Diarrhoea
- Nauseas
- Joint pain
- Life threatening: Immune-related inflammation on lungs, endocrine organs, liver, kidney, sepsis
22
Q
who should avoid taking pembrolizumab for cervical cancer?
A
- Avoid simultaneous taking corticosteroids or immunosuppressants which suppress immune system, as biologics which activate immune system
- NOT SAFE FOR PREGGOS due to increase risk of miscarriage
- Avoid if have hypersensitivity to drug or diluents in infusion
23
Q
whats the signs and Symptoms of Prostate Cancer?
A
- Difficulty urinating
- Low stream of urine
- Frequent urination at night
- Constant need to urinate —> Diaper
- Dark reddish urine
- Weak or swollen lower limbs
- Back pain
24
How is androgen produced?
Hypothalamus intermittently release GnRH to anterior pituitary glands which stimulate testes to produce testosterone —> Testosterone enter cell to be converted into DHT —> DHT enters nucleus of cell and binds to it and activate tumour cell
24
What happens in prostate cancer?
DHT stimulate growth and proliferation of cancer cells —> Develop and spread of cancer tumors —> Enlarge glands compress urethra —> Urinary symptoms
25
how to achieve androgen deprivation for prostate cancer treatment?
1. leuprorelin: Inhibit pituitary gonadotropin release (GnRH)
2. bicalutamide: Inhibit androgen binding
others:
3. finasteride: inhibit androgen synthesis
4. flutamide: inhibit androgen binding
5. surgically remove glands
26
what does prostate growth depend on?
Prostate growth depends on androgens, so androgen deprivation decreases progression of prostate cancer
27
what is an analogue?
Analogue: Structurally similar to another compound but is synthetically created rather than being naturally occurring
28
what is leuprorelin/ leuprolide?
- GnRH agonist —> constant stimulation —> inhibit downstream pathway
- Polypeptide with 10 amino acids
- Synthetic GnRH analogue that acts as agonist at pituitary GnRH receptors
- Not made in body, made in pharmaceutical lab so **can choose amino acids** —> D amino acid is not natural
- 6 injectable products
29
how does leuprorelin work?
- Administered as a continuous or sustained-release formulation
- Initial stage: **Continuous and Intermittent stimulation** of GnRH receptors —> increase in LH and FSH —> stimulate production of testosterone and thus DHT —> DHT binds to androgen receptors in prostate, stimulating growth of prostate tissue —> urinary symptoms BUTBUTBUT
- Over time (~4 weeks): **Continuous** **stimulation** over time **desensitizes** GnRH receptors in the pituitary gland —> **suppression of LH and FSH secretion** —> decrease in production of androgens in testes —> Prostate cancer receives less DHT stimulation —> Shrink and removed by body
note: Continuous: Constant, long-term admin —> desensitize receptors
Intermittent: Cycles of treatment, admin for a period then temporarily stopped —> Not so effective in desensitising receptors
30
what are the biomarkers in bloodstream to identify prostate cancer?
- Prostate-specific antigen (PSA)
- Tens or hundreds in severe stages VS <5 in normal stage
- FH, LSH, Testosterone
31
what is the pkpd (absorption) for leuprorelin for prostate cancer?
- SC or IM
- Single dose long acting: 1, 3 or 4 months interval
- Dose depends on severity of cancer
- Cmax reached within 1-3h after injection
- Stead state reached 4 weeks later
32
what is the pkpd (distribution) for leuprorelin for prostate cancer?
- IV: Apparent volume of distribution of 27L (more than 5L so can be distributed to tissues aka prostate)
- SC and IM: Unknown Vd
- ~45% plasma protein binding in vitro —> testing outside of body to identify extent of binding
33
what is the pkpd (metabolism) for leuprorelin for prostate cancer?
- Polypeptide so broken down by peptidases into inactive peptides
- t1/2 ~3h
- Replaced S amino acid with **Single D amino acid introduced increases circulating half life** from 3-4mins to 3h (advantage of genetic engineering)
- Not metabolised in liver CYP450
34
what is the pkpd (excretion) for leuprorelin for prostate cancer?
<5% excreted in urine
35
what are the side effects when taking leuprorelin for prostate cancer?
- Local pain and redness at injection site
- Hot flushes during first few weeks of treatment
- Headaches and dizziness
- GI disturbances
- Altered mood
- Hyperglycemia
- Decreased libido (sex drive) —> Sad.. boooo
36
who should avoid taking leuproreline for prostate cancer?
- If have hypersensitivities
- Pre-existing heart disease
- Osteoporosis risks (Lesser androgen —> Decrease in bone density)
37
what is bicalutamide for prostate cancer?
- Small molecule: Androgen receptor antagonist aka **antiandrogen**
- 6 oral products: 50-150mg
38
why is bicalutamide not used as monotherapy for prostate cancer?
- **Not used in monotherapy** due to:
- Initial stage: Blocking of androgen receptor increases LH secretion due to **negative feedback** —> higher serum testosterone levels —> so given in combi with GnRH analogue to alleviate effects of testosterone surge (tumor flare)
39
how does bicalutamide work during treatment of prostate cancer?
Competitively binds to androgen receptor in prostate cells —> prevents androgens from binding to receptor —> prevents activation of androgen receptor as inhibits nuclear translocation of androgen receptor —> inhibits signals that promote growth and division of prostate cancer cells —> apoptosis triggered and shrinks cancer cells
40
what is bicalutamide indicated for?
- Prostate cancer
- Androgen deprivation therapy (used during initiation with GnRH agonist to reduce symptoms of tumour flare in patients with metastic prostate cancer)
- Locally advanced disease (with radiation therapy or surgery depending on stage of cancer)
41
whats the pkpda (Absorption) for bicalutamide for prostate cancer?
- Well absorbed so orally
- 50-150mg
- Food does not affect bioavailability
- Taken once a day with GnRH analogue
42
whats the pkpda (distribution) for bicalutamide for prostate cancer?
- High plasma protein bound form
- Has chiral centre so can exist in racemic form —> R (active form) form mainly bound to plasma protein
43
whats the pkpda (metabolism) for bicalutamide for prostate cancer?
- Extensively metabolised in liver
- Metabolism can generate different metabolites due to chiral centre
- Phase 2 metabolism: Rapid **Glucuronidation** to form glucuronide metabolite to be cleared
- Phase 1 metabolism by **CYP3A4**: Slow **CYP450 Hydroxylation** and then Glucuronidation to make more water soluble to be cleared
- t1/2 = 6 days (R isoform)
44
whats the pkpda (excretion) for bicalutamide for prostate cancer?
Parent drug and metabolites excreted via bile (cos metabolised in liver) and faces and urine
45
what are the side effects of bicalutamide for prostate cancer?
- Hot flushes
- N/v
- Loss of libido
- Fatigue
- GI: Constipation/ diarrhoea
- Mild swelling of ankles, legs, feet
46
who should avoid bicalutamide for prostate cancer?
- Women and children (obviously)
- Hypersensitivity
