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3152 finals > cancer drugs > Flashcards

cancer drugs Flashcards

1
Q

Tamoxifen drug

A

SERM (selective estrogen receptor modulator)
Endocrine-based drug
* Reach breast tissue cancer cells
* Penetrate cell
*Enter nucleus, estrogen receptor

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2
Q

tamoxifen MOA

A

1) Competitively blocks endogenous estrogen binding to estrogen receptor in target tissue
2) Tamoxifen-ER complex
3) Alters estrogen-responsive gene expression
4) Prevent cell activation, proliferation

* Estrogenic// anti-estrogenic effects
* Tissue specific effects 
            - Breast, uterus, ovaries
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3
Q

tamoxifen structure

A

CIS: Estrogenic (normal estrogen effect)
TRANS: anti-estrogenic activity (block)

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4
Q

PK of tamoxifen

A

A: given orally. F~100%, rapidly, extensively absorbed in intestine
* Peak 5/ 3-7hrs
* Css reached after 3-4 wks, or ~16wks

D: plasma protein (albumin) binding >98%
* Vd: 50-60l/kg
○ High conc in breast, uterus, ovary, liver, kidney, lung, pancreas
§ Breast: 10x > circ
§ Uterus: 2-3x> circ

M: CL 1.4 ml.min^-1. Kg^-1
t1/2 = 5-7 days (tamoxifen)

E:
○ Mainly eliminated in feces
<1% urine excretion

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5
Q

metabolic pathways for tamoxifen

A
  • Phase 1: hydroxylation, N-oxidation, dealkylation (break down)
  • Major pathway = N-demethylation
    ○ Catalysed by CYP3A4 —> N-desmethyltamoxifen —> CYP2D6 —> endoxifen
    ○ Major metabolite: N-desmethyltamoxifen (t1/2 14 days)
      ○ tamoxifen (cyp2d6) --> 4-OH tamoxifen --> (cyp3a4)  ENDOXIFEN 
      § Minor metabolites
      § Exhibit affinity for ER > tamoxifen
  • Phase 2: glucuronidation, sulphation
    ○ Add large hydrophilic molecules
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6
Q

active metabolites effect

A

4-OH tamoxifen & endoxifen

compete for ER with tamoxifen
greater affinity than tamoxifen, reduce therapeutic effects

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7
Q

potential tamoxifen DDI

A

CYP3A4: grapefruit
CYP2D6: diphenhydramine (cough, cold)

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8
Q

tamoxifen indicated for

A
  • Breast cancer (early/ metastatic)
  • Pre/ post menopausal
  • Chemoprevention in women w/ high risk
    • Family hist
    • Genetic predisposition
  • Reduce severity of osteoporosis (good SE, but not main indication)
    - Other agents with better SE profile
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9
Q

SE of tamoxifen

A
  • Hot flashes
  • High risk of endometrial cancer
    ○ Cis isomers accumulate in ovaries, uterus
    ○ Regular monitoring required
    § Menstrual irregularities
    § Vaginal bleeding and discharge
  • Venous thromboembolic events (DVT)
  • NV

Toxicity:
* High doses, lead to acute nephrotoxicity
○ Tremor, hyperreflexia, unsteady gait, dizziness
* Pt experience overdose: given supportive treatment
○ No specific treatment

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10
Q

Pembrolizumab drug

durable immune effects

A

T cell immunotherapy (immune checkpt inhibitors) is a PD1 blockers

	1. PDL1- (cancer cell)
		i. competes with PDL1 receptor
		ii. No longer shield, stop growth
	2. So t cell receptors PD1 receptor can bind and attack
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11
Q

MOA of Pembrolizumab

A
  • Death receptor (PD-1) on T cell
  • Pembrolizumab is PD-1 blocker, binds to T cell PD-1 receptor
  • Allow release of PD-1 pathway-mediated T cell activities
    - Prevent PDL1 ligand on cancer to inhibit T cell mediated immune response
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12
Q

structure of pembrolizumab

A
  • Humanised Ab (90%)
    ○ Recombinant from CHO cells
    ○ Inhibit cancer metastasis
    ○Only the CDR is chimeric

○ CDR: hypervariable region of Ig - bind epitope
responsible for antigen specificity and affinity of AB

replace all but hypervariable CDR domains

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13
Q

PK of pembrolizumab

A

A: administered parenterally IV
* IV 200mg, every 3 wks

D: Vd small, ~7L
* Limited extravascular distribution
* Not bind to plasma proteins in specific manner
* Stay in circ

M: cleared from circ in non-specific catabolism
○ No metabolic drug interactions
* T1/2: 27 days, may reach Css after 19 wks
Affect CL:
1. Albumin (protein) and bilirubin lvl
2. Type of cancer
3. Gender (lower CL F>M)
a. Affects dosing

E: limited study on elimination route

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14
Q

non-specific catabolism

A
  • Break down large mole into smaller units
    • –> small peptides, aa by protein degradation
      ○ No metabolic drug interactions
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15
Q

ADR of pembrolizumab

A
  • Infusion-related SE (hypersensitivity to drug and components)
    ○ Rash
    ○ Itchiness
  • Fatigue
  • Diarrhea
  • Nausea
  • Joint pain
  • Life-threatening immune-related inflammation
    ○ Lung, endocrine organs, liver, kidney, sepsis
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16
Q

CI of pembrolizumab

A
  • Pt on CS/ immunosuppressants
    ○ Must be stopped before taking pembrolizumab <– immune related inflammation
    § Then add back CS afterwards
    ○ Interfere with ADR
  • Pregnant women – miscarriage
  • History of severe reactions:
    ○ Hypersensitivity to other biologics
    ○ other illnesses (infection, liver/ kidney disease)
17
Q

prostate cancer signs and sx

A
  • Difficulty urinating
  • Low stream of urine
  • Freq urination at night (affect QOL)
  • Constant need to urinate
  • Dark red urine
  • Weak, swollen lower limbs
  • Back pain
18
Q

prostate growth depends on androgens.
androgen deprivation, reduce progression of prostate cancer.

ways to achieve androgen deprivation?

A

1) Inhibit pituitary gonadotropin release (GnRH)
Leuprorelin, leuprolide

2) Inhibit androgen synthesis
Finasteride

3) Inhibit androgen binding – androgen receptor blockers
flutamide, Bicalutamide

4) Surgical extirpation of glands: castration, adrenalectomy (remove 1-2 testicles to reduce testosterone)

19
Q

Leuprorelin drug

A

Targets upstream GnRH agonists

20
Q

MOA of leuprorelin

A

1) Continuous administration, constant GnRH release into pituitary gland
2) Suppress FSH, LH release
3) Decr androgens synthesis (testosterone release)
4) Minimise +ve stimulating effect on androgen sensitive prostate cancer cell
a) Cancer cell apoptosis

21
Q

monitor for leuprorelin therapy

A
  • prostate-specific antigens (PSA) in first few wks of therapy
    ○ Biomarker if prostate is hyperactive
    ○ Enlarged prostate? Benign prostatic hyperplasia? Cancer?
  • FSH, LH, serum testosterone after 4 wks therapy
    May incr at start due to incr GnRH
22
Q

structure of leuprorelin

A

Synthetic GnRH analogue
Acts as agonist at pituitary GnRH receptors

23
Q

PK of leuprorelin

A

A: SC/ IM (single dose Long-Acting depot)
* 1,3,4 mnths interval
* Cmax: 1-3hrs post injection
* Css reached typically after 4wks

D: Vd ~27L after Iv
* No data on Vd after SC/ Im
* Display 45% plasma protein binding (in vitro) - not much data

M: degraded proteolytically by peptidases
* Into inactive peptides
○ Not metabolised in liver (CYP450)
* T1/2~ 3hr

E: <5% unchanged in urine

24
Q

ADR of leuprorelin

A
  • Local pain at inj site (~10% cases)
  • Flushes
  • Headaches/ migraine
  • GI disturbances
  • Altered mood
  • Hyperglycemia
  • Hyperlipidemia
    *Loss of libido, impotency
25
Q

CI of leuprorelin

A
  • Hypersensitivity to Leuprorelin. Other GnRh agonist
  • Pre-exist heart disease
  • Pt risk of osteoporosis
    - Incr fall risk due to low bone density
26
Q

Bicalutamide drug

A

Direct blockade of hormone acting on its receptor
Androgen receptor ANTAGONIST
** not for monotherapy
** combi w/ GnRH analogue (alleviate symptoms of testosterone surge in GnRH agonists)

fast onset, relieve sx

27
Q

MOA of bicalutamide

A

1) Blocks AR, inhibit action of androgens
- Competitive antagonise androgen receptor
- Inhibit nuclear translocation of AR
-Inhibit interaction of AR with promoter at AR response element

2) Inhibition of AR-dependent transcription
- Impairs cell proliferation
- Trigger apoptosis in cancer cells

3) Decr androgen, prevents prostate growth
- Decr progression of prostate cancer

4) Incr LH secretion/ FSH –> stimulate body to incr serum testosterone levels (undesirable outcome, when monotherapy)

28
Q

structure of bicalutamide

A

Chiral centre, forms R/S isomers

29
Q

structure of bicalutamide relating to its metabolism

A

Chiral centre, forms R/S isomers

  • (S) -bicalutamide
    ○ Inactive alr, goes to phase 2
    ○ Glucuronidation
  • (R)- bicalutamide
    ○ Active, goes phase 1 –> 2
    ○ P1: Hydroxylation (CYP3A4)
    ○ P2: Glucuronidation
30
Q

PK of bicalutamide

A

A: OD PO tablet
* Conjunction with GnRH analogue

D: highly plasma protein bound (albumin)

M: liver, stereoselective
* (S) -bicalutamide
○ Inactive alr, goes to phase 2
○ Glucuronidation

* (R)- bicalutamide 
	○ Active, goes phase 1 --> 2
	○ P1: Hydroxylation (CYP3A4)
	○ P2: Glucuronidation 
* T1/2 ~ 6 days

E: bile, urine

31
Q

ADR of bicalutamide

A
  • Gynecomastia
  • Sexual dysfunction
  • Fatigue
  • GI disturbances
  • Seizures (rare)
32
Q

bicalutamide indicated when

A
  • Prostate cancer
  • Androgen deprivation therapy
  • Locally advanced disease

In conjunction To incr survival
* with radiation therapy
* With surgery

3152 finals (9 decks)

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