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endocrine cancer Flashcards

1
Q

what are the meds used for endocrine cancer?

A
  1. Tamoxifen
  2. Pembrolizumab
  3. Leuprorelin
  4. Bicalutamide

just rmb: tplb: tammy’s pen leaks bicarbonate

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2
Q

which meds are small molecules? which are big molecules?

A

small: Tamoxifen
big: Pembrolizumab

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3
Q

what are the indications for the following drugs?

A
  1. Tamoxifen: breast cancer
  2. Pembrolizumab: cervical cancer
  3. Leuprorelin: prostate cancer
  4. Bicalutamide: prostate cancer
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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
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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
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6
Q

what effects does tamoxifen for breast cancer provide? what is the structure?

A
  1. Exhibits estrogenic + anti-estrogenic effects
  2. Exhibits tissue-specific effects
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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
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7
Q

how does tamoxifen for breast cancer Exhibits tissue-specific effects?

A

Depends on apparent volume of distribution

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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
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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
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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)
    • Second metabolite
      • Endoxifen (most active tamoxifen)
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11
Q

what is the pkpd (excretion) for tamoxifen for breast cancer?

A

Not alot in urine since liver metabolism

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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

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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)
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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
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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

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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
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17
Q

what is prembrolizumab?

A

Biologic (big molecule), Antibody (-mab);

used for Cervical cancer

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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

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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
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
Q

How is androgen produced?

A

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
Q

What happens in prostate cancer?

A

DHT stimulate growth and proliferation of cancer cells —> Develop and spread of cancer tumors —> Enlarge glands compress urethra —> Urinary symptoms

25
Q

how to achieve androgen deprivation for prostate cancer treatment?

A
  1. leuprorelin: Inhibit pituitary gonadotropin release (GnRH)
  2. bicalutamide: Inhibit androgen binding

others:
3. finasteride: inhibit androgen synthesis
4. flutamide: inhibit androgen binding

  1. surgically remove glands
26
Q

what does prostate growth depend on?

A

Prostate growth depends on androgens, so androgen deprivation decreases progression of prostate cancer

27
Q

what is an analogue?

A

Analogue: Structurally similar to another compound but is synthetically created rather than being naturally occurring

28
Q

what is leuprorelin/ leuprolide?

A
  • 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
Q

how does leuprorelin work?

A
  • 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
Q

what are the biomarkers in bloodstream to identify prostate cancer?

A
  • Prostate-specific antigen (PSA)
    • Tens or hundreds in severe stages VS <5 in normal stage
  • FH, LSH, Testosterone
31
Q

what is the pkpd (absorption) for leuprorelin for prostate cancer?

A
  • 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
Q

what is the pkpd (distribution) for leuprorelin for prostate cancer?

A
  • 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
Q

what is the pkpd (metabolism) for leuprorelin for prostate cancer?

A
  • 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
Q

what is the pkpd (excretion) for leuprorelin for prostate cancer?

A

<5% excreted in urine

35
Q

what are the side effects when taking leuprorelin for prostate cancer?

A
  • 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
Q

who should avoid taking leuproreline for prostate cancer?

A
  • If have hypersensitivities
  • Pre-existing heart disease
  • Osteoporosis risks (Lesser androgen —> Decrease in bone density)
37
Q

what is bicalutamide for prostate cancer?

A
  • Small molecule: Androgen receptor antagonist aka antiandrogen
  • 6 oral products: 50-150mg
38
Q

why is bicalutamide not used as monotherapy for prostate cancer?

A
  • 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
Q

how does bicalutamide work during treatment of prostate cancer?

A

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
Q

what is bicalutamide indicated for?

A
  • 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
Q

whats the pkpda (Absorption) for bicalutamide for prostate cancer?

A
  • Well absorbed so orally
  • 50-150mg
  • Food does not affect bioavailability
  • Taken once a day with GnRH analogue
42
Q

whats the pkpda (distribution) for bicalutamide for prostate cancer?

A
  • High plasma protein bound form
  • Has chiral centre so can exist in racemic form —> R (active form) form mainly bound to plasma protein
43
Q

whats the pkpda (metabolism) for bicalutamide for prostate cancer?

A
  • 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
Q

whats the pkpda (excretion) for bicalutamide for prostate cancer?

A

Parent drug and metabolites excreted via bile (cos metabolised in liver) and faces and urine

45
Q

what are the side effects of bicalutamide for prostate cancer?

A
  • Hot flushes
  • N/v
  • Loss of libido
  • Fatigue
  • GI: Constipation/ diarrhoea
  • Mild swelling of ankles, legs, feet
46
Q

who should avoid bicalutamide for prostate cancer?

A
  • Women and children (obviously)
  • Hypersensitivity

finals (8 decks)

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