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PR3152 > Pharmacology - Endocrine Cancers > Flashcards

Pharmacology - Endocrine Cancers Flashcards

1
Q

What is tamoxifen indicated for?

A
  • Early and metastatic breast cancer, in both pre and post-menopausal women
  • May be useful in chemoprevention of breast cancer in women at high risk
  • Reduces severity of osteoporosis but is not specifically used for osteoporosis due to availability of agents with superior side effect profiles
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2
Q

What is the mechanism of action of tamoxifen?

A
  • Competitively blocks endogenous estrogen binding to the estrogen receptor in the target
  • Tamoxifen then deactivates the AF2 transcription site (AF1 site is still active), which then serves as a partial blocker to alter estrogen-responsive gene expression → ↓ cancer cell activation & proliferation
  • Exhibits estrogenic (cis-isomer) and anti-estrogenic (trans-isomer) effects
  • Exhibits tissue-specific effects
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3
Q

What is the bioavailability of tamoxifen?

A

~100%

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4
Q

How is tamoxifen absorbed?

A

Rapidly and extensively absorbed in intestine

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5
Q

Does tamoxifen bind to plasma proteins?

A

Yes, >98%

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6
Q

What is the Vd of tamoxifen?

A

50-60L/kg

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7
Q

How does tamoxifen distribute in the body?

A

Concentrates well in the breast, uterus, liver, kidney, lung, pancreas, ovaries (uterus cons are 2-3x of circulatory conc, breast conc is 10x)

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8
Q

What is the elimination half-life of tamoxifen?

A

5-7 days

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9
Q

How is tamoxifen metabolised?

A

CYP3A4 -N-desmethyl-tamoxifen
CYP2D6 - 4-OH-tamoxifen

both get metabolised by the other CYP enzyme to endoxifen

Phase 1: Hydroxylation, N-oxidation, dealkylation
Phase 2: Glucuronidation, sulphation

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10
Q

What are the adverse effects of tamoxifen?

A
  • Hot flashes (non-dose related)
  • Increases risk of endometrial cancer
  • Venous thromboembolic events (DVT)
  • Menstrual irregularities
  • Vaginal bleeding and discharge
  • Nausea, vomiting
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11
Q

What are the effects of tamoxifen toxicity?

A

Acute neurotoxicity (tremor, hyperreflexia, unsteady gait, dizziness)

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12
Q

What is the MOA of pembrolizumab?

A

Binds to PD-1 on T cells to block PD-L1 on cancer cells from binding to PD-1 – PD-L1 binding to PD-1 inhibits T cell activation so that cancer cells can evade immune response (inhibited by Pembrolizumab)

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13
Q

How is pembrolizumab administered?

A

IV

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14
Q

What is the Vd of pembrolizumab?

A

~7L - small because it is a protein molecule

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15
Q

What is the half-life of pembrolizumab?

A

~27 days

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16
Q

How long does it approximately take for pembrolizumab to reach Css?

A

19 weeks

17
Q

How is pembrolizumab cleared?

A

Cleared from circulation through non-specific catabolism (because it is a protein)

18
Q

What are the adverse effects of pembrolizumab?

A
  • Infusion related SEs – rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, fever
  • Fatigue
  • Diarrhoea
  • Nausea
  • Joint pain
  • (Life-threatening) Immune related inflammation on lung, endocrine organs, liver, kidney
  • (Life-threatening) Sepsis
19
Q

What are the contraindications for pembrolizumab?

A
  • Taking corticosteroids or immunosuppressants – stop before starting pembrolizumab (starting afterwards is fine)
  • Pregnancy – may inc miscarriage risk
  • Hx of severe reaction to another antibody therapy eg hypersensitivity
  • Hx of other illnesses – infection, liver/kidney diseases etc (consult dr – risk of opportunistic infection)
20
Q

What is leuprorelin indicated for?

A

Prostate cancer

21
Q

What is the MOA of leuprorelin?

A
  • A synthetic GnRH analogue – acts as agonist at pituitary GnRH receptors
  • Decreases androgen (testosterone) production in testes to minimise stimulation of androgen-sensitive prostate cancer cells so that the cancer cells undergo apoptosis
  • Continuous administration decreases FSH and LH release to suppress androgen synthesis (as compared to intermittent GnRH which increases FSH and LH instead)
22
Q

How is leuprorelin administered?

A

SC or IM as a single-dose long-acting depot (interval can vary – 1, 3 or 4/12)

23
Q

How long does it take for leuprorelin to reach Cmax?

A

1-3h

24
Q

How long does it take for leuprorelin to reach Css?

A

4 weeks

25
Q

What is the Vd of leuprorelin?

A

Vd ~27L after IV

26
Q

Does leuprorelin bind to plasma proteins?

A

In-vitro displayed ~45% plasma protein binding

27
Q

How is leuprorelin metabolised?

A

Degraded proteolytically (potentially by peptidases) into inactive peptides

28
Q

What is the half-life of leuprorelin?

A

~3h

29
Q

How is leuprorelin excreted?

A

<5% by urine

30
Q

What are the adverse effects of leuprorelin?

A
  • Local pain and redness at injection site (~10% of cases)
  • Hot flushes during first few weeks of Tx
  • Headaches/dizziness
  • GI disturbances
  • Altered mood
  • Hyperglycemia
  • Decreased libido (may need to take not depending on whether patient is still sexually active)
31
Q

What are the contraindications for leuprorelin?

A
  • Hypersensitivity to Leuprorelin or other GnRH agonists
  • Pre-existing heart disease
  • Patients with risk for osteoporosis
32
Q

What are the indications for bicalutamide?

A
  • Prostate cancer
  • Androgen deprivation therapy – used during initiation of androgen deprivation therapy w an LHRH agonist to reduce the symptoms of tumor flare in metastatic prostate cancer patients
  • For locally advanced disease – in conjunction w radiation tx or surgery (start bicalutamide first, then see if response is enough to not need further radiation or surgery)
33
Q

What is the MOA of bicalutamide?

A
  • Competitively antagonises androgen receptor
  • Inhibits nuclear translocation of the androgen receptor and interaction of the androgen receptor response element – impairs cell proliferation and triggers apoptosis in cancer cells
  • Androgen deprivation decreases prostate growth rate, thus slowing down progression of prostate CA
34
Q

How is bicalutamide absorbed?

A

Well absorbed orally, food does not affect F

35
Q

Does bicalutamide bind to plasma proteins?

A

Yes, highly plasma protein bound
(racemic mixture 96%, R-bicalutamide >99%)

36
Q

How is bicalutamide metabolised?

A

Extensively metabolised in the liver, T1/2 ~6 days (R-isomer)
- S-isomer (inactive) rapidly cleared by glucuronidation
- R-isomer (active) slowly cleared by CYP3A4 hydroxylation, then glucuronidation

37
Q

How is bicalutamide excreted?

A

Parent drug and metabolites excreted by faeces and urine

38
Q

What are the adverse effects of bicalutamide?

A
  • Hot flushes
  • Nausea, vomiting
  • Dec sexual desire/ability (may need to take note of if patient is still sexually active)
  • Fatigue
  • Constipation/diarrhoea
  • Mild swelling of ankles, legs and/or feet
39
Q

What are the contraindications for bicalutamide?

A
  • Women and children
  • Patients with known hypersensitivity reaction to bicalutamide or any of the excipients

PR3152 (5 decks)

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