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3152 Endocrine (DM + Thyroid) > Endocrine Cancers > Flashcards

Endocrine Cancers Flashcards

1
Q

What drug is used in breast cancer?

A

Tamoxifen (oral tablet)

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2
Q

Describe Tamoxifen MOA

A

Selective estrogen receptor modulator (SERM)
*Anti-estrogenic

Competitively blocks endogenous estrogen binding to the ER in the target tissue (breast)
Form Tamoxifen-ER complex that alters estrogen-responsive gene expression (inactivates transcription)
Prevent cell activation and proliferation

*Cancer cells use estrogen hormone to grow, hence block estrogen binding to the ER to slow cancer growth

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3
Q

Explain why Tamoxifen exhibits both estrogenic and anti-estrogenic effect

A

*Alkene group in the structure

Cis-isomer: estrogenic activity
Trans-isomer: anti-estrogenic activity

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4
Q

List the clinical uses of Tamoxifen

A
  1. Breast cancer (in both pre and post menopausal women)
  2. Chemoprevention of breast cancer in women at high risk (e.g., FH, genetic predisposition)
  3. (NOT USED FOR THIS INDICATION) Reduce severity of osteoporosis - estrogen regulates bone density
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5
Q

Describe the absorption profile of Tamoxifen

A

Rapidly absorbed in intestine, bioavailability of 100%

Takes 3-4 weeks (up to 16 weeks) to reach steady tate

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6
Q

Describe the distribution profile of Tamoxifen

A

Plasma protein binding >98%

High Vd 50-60L/kg

Tamoxifen concentrates in breast, uterus, liver, kidney, lung, pancreas, ovary tissues

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7
Q

Describe the metabolism profile of Tamoxifen

A

Phase 1: Hydroxylation, N-oxidation, dealkylation

Phase 2: Glucoronidation, sulphation

Major pathway: N-demethylation (catalysed by CYP3A4) => N-desmethyl-tamoxifen
*N-desmethyl-tamoxifen can be metabolised via CYP2D6 to Endoxifen

Alternative: CYP2D6 => 4-OH tamoxifen => CYP3A4 => Endoxifen

*Endoxifen is also known as 4-hydroxy-N-desmethyltamoxifen

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8
Q

Which metabolites of Tamoxifen have estrogenic activity as well

A

CYP2D6 metabolites: 4-OH Tamoxifen and Endoxifen (4-hydroxy-N-desmthyltamoxifen)

These minor metabolites exhibit greater affinity for the ER than Tamoxifen

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9
Q

What are some DDI or FDI that can occur with Tamoxifen?

A

Grapefruit juice: inhibits CYP3A4

Diphenhydramine: inhibits CYP2D6

=> Incr Tamoxifen levels

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10
Q

Describe the elimination profile of Tamoxifen

A

Eliminated mainly via feces

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11
Q

What are some SEs of Tamoxifen?

A
  1. Hot flushes - think low levels of estrogen (menopausal effects)
  2. Incr risk of endometrial (uterus) cancer - think accumulation of cis isomer
  3. Venous thromboembolic events (DVT)
  4. Menstrual irregularities - early sign of endometrial cancer
  5. Vaginal bleeding and discharge - early sign of endometrial cancer
  6. Nausea, vomiting
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12
Q

What are some toxicity issues with high doses of Tamoxifen?

A

High doses => acute neurotoxicity (tremor, hyperreflexia, unsteady gait, dizziness)

*Overdose - supportive treatment (no antidote)

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13
Q

What drug is used in cervical cancer?

A

Pembrolizumab (biologic) - IV, parenteral

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14
Q

What is the MOA of Pembrolizumab?

A

Checkpoint inhibitor (PD-1 blocker)

Binds to PD-1 on T cells, prevent binding of PD-L1 on cancer cells to PD-1, therefore prevent PD-1 pathway-mediated inhibition of T-cell activities
=> basically T cell can now kill the cancer cell

Inhibit cancer metastasis

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15
Q

How is Pembrolizumab manufactured?

A

Humanized antibody
- recombinantly manufactured from CHO cells

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16
Q

Describe Pembrolizumab absorption profile

A

Parenteral (IV)

200mg IV, every 3 weeks (may last longer than >8months)
Css after 19 weeks

17
Q

Describe Pembrolizumab distribution profile

A

Small Vd 7L
Limited extravascular distribution (mostly limited to blood circulation)
Not expected to bind to plasma protein in a specific manner

18
Q

Describe the metabolism of Pembrolizumab

A

Non-specific catabolism (general protein degradation of large mAb into small peptides and AAs)

E.g., lysosomal degradation, proteasomal degradation

19
Q

What are some factors affecting the clearance of Pembrolizumab

A

Gender - clearance lower in females
Albumin (plasma protein) levels, bilirubin levels
Types of cancer

20
Q

What are the SEs of Pembrolizumab?

A
  1. Infusion-related SE: rash, itchiness, hypersensitivity to drug components
  2. Fatigue
  3. Diarrhea
  4. Nausea
  5. Joint pain
  6. Life-threatening immune related inflammation of lungs, endocrine organs, liver, kidney
  7. Sepsis
21
Q

What are the contraindications of Pembrolizumab?

A

Corticosteroids and Immunosuppressants

  • Stop before starting Pembrolizumab as immunosuppressive effects may interfere with action of Pembrolizumab
  • May be used after Pembrolizumab to deal with immune-related adverse events

Pregnant women

  • incr risk of miscarriage

History of severe reaction (hypersensitivity) to other antibody therapy

Patients with other illnesses (infections, liver/kidney disease) => consult doctor

22
Q

What are the signs and symptoms of prostate cancer?

A
  1. Difficulty urinating
  2. Low stream of urine
  3. Frequent urination at night
  4. Constant need to urinate
  5. Dark reddish urine
  6. Weak or swollen lower limb
  7. Back pain
23
Q

What are the 4 methods used to treat prostate cancer?

*Androgen (testosterone) deprivation - as androgen promotes growth of normal and cancerous prostate cells by binding to and activating the androgen receptor on prostate cells

A
  1. GnRH analogs (Leuprorelin/Leuprolide)
  • Inhibit pituitary gonadotropin (LSH/FH) release
  1. 5-alpha reductase inhibitor (Finasteride)
  • Inhibit androgen synthesis (prevent testosterone to DHT)
  1. Androgen receptor blockers (Flutamide, Bicalutamide)
  • Inhibit androgen binding to androgen receptor
  1. Surgical extirpation of the glands (Castration, adrenalectomy, orchiectomy)
  • remove testes to reduce testosterone levels
24
Q

Describe the MOA of Leuprorelin (SC/IM)

A

Synthetic gonadotropin releasing hormone (GnRH) analogue, acts as agonist at pituitary GnRH receptor (in CNS)

Continuous administration of GnRH agonist cause desensitization of GnRH receptor, leading to decrease LH and FSH release, and thus suppression of androgen synthesis
(*recall that normal circumstance: intermittent GnRH release in pulses)

*Decrease androgen => dcr growth and proliferation of androgen-sensitive prostate cancer cells => apoptosis => decrease progression of prostate cancer

25
Q

What are the monitoring parameters for Leuprorelin treatment

A
  1. PSA (prostate-specific antigen): higher PSA means enlarged prostate
    => should decrease in first few weeks of therapy
  2. LH, FSH, serum testosterone levels (after 4 weeks of therapy)
26
Q

Describe the absorption profile of Leuprorelin

A

SC/IM given as single dose long-acting depot @ 1, 3, or 4 months interval
Cmax 1-3h post injection
Css after 4 weeks

27
Q

Describe the distribution profile of Leuprorelin

A

45% plasma protein binding in vitro
Vd 27L after IV (no info on SC or IM)

28
Q

Describe the metabolism of Leuprorelin

A

It is a polypeptide, degraded proteolytically (potentially by peptidases)

29
Q

Describe the elimination of Leuprorelin

A

<5% excreted unchanged via urine

30
Q

What are the SEs of Leuprorelin?

A
  1. Local pain at injection site
  2. Flushes
  3. Headache/migraine
  4. GI disturbances
  5. Altered mood
  6. Hyperglycemia
  7. Hyperlipidemia
  8. Loss of libido, impotence
31
Q

What are the contraindications with Leuprorelin?

A
  1. Hypersensitivities to Leuprorelin or other GnRH agonists
  2. Preexisting heart disease
  3. Pt at risk for osteoporosis
32
Q

What is the MOA of Bicalutamide?

A

Androgen receptor antagonist

Competitively antagonizes the AR

  • Inhibit nuclear translocation of the AR from cytoplasm into nucleus
  • Inhibit interaction of AR with AR response element in the nucleus
  • Inhibit AR-dependent transcription
  • Impair cell proliferation and trigger apoptosis in cancer cells

*Decrease androgen => dcr growth and proliferation of androgen-sensitive prostate cancer cells => apoptosis => decrease progression of prostate cancer

33
Q

Why is Bicalutamide not used as monotherapy for prostate cancer?

A

Blocks AR => incr LH secretion (due to negative feedback) => higher serum testosterone levels

*Initial surge in LH and testosterone

*NOT used as monotherapy for prostate cancer - use with GnRH analogue
=> alleviate effects of testosterone surge

34
Q

What are the clinical uses of Bicalutamide?

A
  1. Prostate cancer
  2. Androgen deprivation therapy
  3. Locally advanced disease - advanced stage of prostate cancer (in conjunction with radiation therapy or surgery, to increase survival)
35
Q

Describe the absorption of Bicalutamide

A

Oral, once daily in combi with GnRH analogue

36
Q

Describe the distribution of Bicalutamide

A

Highly plasma protein bound (albumin)

37
Q

Describe the metabolism of Bicalutamide

*Take note of stereoisomers

A

Metabolised in the liver

Stereoselective (due to chiral center)

  • S-bicalutamide (inactive): phase 2 glucuronidation
  • R-bicalutamide (active): phase 1 hydroxylation via CYP3A4, phase 2 glucuronidation
38
Q

Describe the elimination of Bicalutamide

A

Eliminated in bile and urine

39
Q

What are the SEs of bicalutamide?

A
  1. Gynecomastia
  2. Sexual dysfunction
  3. Fatigue
  4. GI disturbances
  5. Seizure (rare)

3152 Endocrine (DM + Thyroid) (11 decks)

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