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Pharmacology & Medical Chemistry II > Exam 3: Lecture 1,2,3 Pharmacology of Cancer Drugs > Flashcards

Exam 3: Lecture 1,2,3 Pharmacology of Cancer Drugs Flashcards

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1
Q

What is cancer?

A

Disease characterized by uncontrolled proliferation of abnormal cells.

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2
Q

Growth Characteristics of the malignant cell?

A

Genetic change
Uncontrolled proliferation
Invasiveness
Metastasis

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3
Q

G0 phase….

A

cell does not actively divide, doing whatever it does

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4
Q

How will cell go from G0 to G1?

A

gets signal

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5
Q

S phase…

A

Synthesis

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6
Q

G2 phase….

A

prepare for mitosis

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7
Q

M phase….

A

Mitosis occurs

1 cell differentiates to perform predetermined function
1 cell is able to divide if it gets stimulus

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8
Q

What makes cancer cells different?

A

2 new cells will retain ability to divide and they will proliferate without stimulus…leading to increase in cell mass

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9
Q

Classes of antineoplastic

A

Chemotherapy
Hormones
Targeted therapy

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10
Q

Classes of chemotherapy

A 
Alkylating agents
antibiotics
Antimetabolites
Natural products
Miscellaneous agents
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11
Q

Classes of Targeted therapy?

A

Monoclonal antibodies
Tyrosine Kinase inhibitors
Many others

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12
Q

MOA Alkylators

A

positively charged ethylene ammonium ion binds to electron-rich nucleophilic sites on DNA

Causes:
intra/inter strand cross linking
DNA breaks
DNA mis-reading

Cell cycle non-specific, any phase

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13
Q

Cyclophosphamide (Cytoxan)

A

Absorption – 75% bioavailable PO

Distribution: crosses placenta, appears in milk. So no preg or nursing women.

Metabolism/elimination:
Hepatic activation to active and toxic metabolites
Renal elimination – T ½ 4 – 6 hours

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14
Q

Universal side effects fo chemo agents?

A

Myelosupppression
nausea and vomiting
alopecia

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15
Q

Cyclophosphamide (Cytoxan) adverse effects

A

Gonadal suppression
Hemorrhagic Cystitis ~15% pt
Cardiotoxicity

+ universal side effects

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16
Q

Myelosuppression

A

WBC will drop, hit nadir and then recover

recover occurs around 3rd week, which is why regimens are given every 3 weeks

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17
Q

Nadir is…

A

time of maximal bone marrow suppression

usually around day 8-10

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18
Q

cells affected by Myelosuppression…

A 
WBC (Granulocyte disappear fastest, due to shortest life span)
Platelet
Erythrocyte (don't see much drop due to long life span)

make sure to draw someones blood before giving drug

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19
Q

Ifosfamide

A

sister drug for Cyclophosphamide

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20
Q

Ifosfamide Pharmacokinetics

A

Only given IV

Crosses placenta/milk

Hepatic activation to active and toxic metabolites

half life = 6 hrs

much slower activation than cyclophosphamide, dose higher

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21
Q

Ifosfamide Adverse effects

A

CNS toxicity, crosses BBB

Hemorragic cystitis much more common ~50%+

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22
Q

Hemorrhagic cystitis

A

Due to acrolein, which is toxic to bladder causing inflammation of bladder

Signs/Symptoms:
Blood in urine
pain when peeing
urinary frequency
Lower Abdominal Pain
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23
Q

Hemorrhagic cystitis prevention

A

lots of hydration, drink a lot of water

MESNA

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24
Q

MESNA

A

dimerized in urine, binds to acrolein and inactivates it so it cant effect bladder wall and prevent development of Hemorrhagic Cystitis

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25
Q

3 Nitrosoureas…

A

Carmustine
Lomustine
Streptozocin

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26
Q

Lomustine available only in….

A

tablet (PO) form

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27
Q

Carmustine available in….

A

Iv and Wafers (insertion into brain)

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28
Q

Pharmacokinetics of Carmustine & Lomustine

A

Carmoustine - systemic absorb of wafers uneval
Lomustine - rapidly absorb after PO admin

Distribution: Cross BBB, distribute into milk

Active hepatic metabolism and urinary elimination

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29
Q

Nitrosourea adverse effects

A

SEVERE nausea and vomiting
Delayed mylosuppression***, true nadir around week 4
Alopecia
Chronic Nephrotoxicity and Pulmonary toxicity

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30
Q

How often nitrosourea given?

A

every 6 weeks due to mylosuppression

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31
Q

Platinum-based agents

A

Cispaltin
Carboplatin
Oxaliplatin

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32
Q

Cisplatin Pharmacokinetics

A

Mostly given IV

Eliminated renally

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33
Q

All Platins are excreted through….

A

The urine

have to be mindful of patients kidney situation for dose

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34
Q

“Platinum” Adverse effects

A

Cisplatin - 90% nausea/vomiting
Carboplatin/Oxaliplatin ~ 50%

Myelosuppresson = Dose limiting with Carboplatin, moderate others

Renal damage = only common Cisplatin

neurotoxicity = chronic Cisplatin, Dose limiting Oxaliplatin

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35
Q

Cisplatin Nephrotoxicity

A

Acute renal failure
Dose related and cumulative
Risks: Dehydration, other nephrotoxic drugs

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36
Q

Electrolyte disorders with Platins….

A

Mostly effect Potassium and Magnesium, decrease all

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37
Q

Cisplatin Neurotoxicity

A

Around 300mg/m2 dose

can progress after drug d/c’d

Symptoms: loss of feeling, loss of proprioception, vibration sense, leg weakness, gait disturbances, deep tendon reflexes

40% have chronic complaint, may go away

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38
Q

Oxaliplatin neurotoxicity

A

both acute and chronic

Actue = 30-55% pt, happens in ours to days
Cold food can cause numbness, resolve after few weeks

Chronic = dose related/cumulative
may improve when D/c

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39
Q

cisplatin Ototoxicity

A

high frequency hearing loss

dose related, cumulative, maybe irreversible

uncommon with other platins

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40
Q

Cisplatin Regimin

A

20mg/m2 X 5 days X every 3 weeks (Ball cancer)

50-100 mg/m2 every 3-4 weeks (Other solid tumors)

Make sure patient well hydrated so doesn’t sit in kidney

Taxane given first if given with platin

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41
Q

Carboplatin Regimin

A

360 mg/m2 every 4 weeks alone
300 mg/m2 every 4 weeks with CTX

no need for hydration

Taxane first

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42
Q

Calvert Formula

A

formula for given Carboplatin

if prior chemo, AUC = 4-6
no prior chemo, AUC 6-8

Total dose = AUC (GFR + 25)

not tested in children

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43
Q

cautions with Platin

A

don’t use with Aluminum ie needles

Cisplatin solution must contain chloride*
Carboplatin ok to be in NS, D5W*
Oxaliplatin needs to avoid chloride solution***

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44
Q

Temozolamide

A

Given IV or PO

Degrades to MTIC

Good penetration across BBB….brain tumors

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45
Q

Doxorubicin family MOA

A

Drug binds to DNA through intercalation

Topoisomerase II inhibition, can cut but not glue

form free radicals, except mitoxantrone

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46
Q

What does Topoisomerase do?

A

creates openings by cutting strands of DNA, allowing them to cross one another

“Glues” them back

if DNA isn’t “pasted” together correctly = cell die

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47
Q

Doxorubicin family Pharmacokinetics

A

Poor oral absorption, given IV

Distributed rapidly throughout body, poor CNS

Primary elimination is hepatic metabolism but also eliminated by kidney. can change color of pee (red/pinkish)

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48
Q

color that mitoxantrone will make pee?

A

blue or greenish

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49
Q

doxorubicin family Adverse effects

A

Myelosuppression
GI stuff
Hairloss, entire body
Hyperpigmentation and local tissue damage

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50
Q

Extravasation

A

leaking out of vein into tissue

given by slow push to avoid it

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51
Q

Prevention and management of extravasation

A

frequent monitoring of site
assure needles is in vein

if it occurs;
aspirate drug out of area
corticosteroids
Heat/ice
Dexrazoxane (Totect)** for doxorubicin
skin graft if severe
52
Q

Radiation recall

A

pt who has had radiation therapy, will get same reaction when given drugs in doxorubicin family

usually within few months of completing radiation therapy

53
Q

All drugs in Doxorubicin family are….

A

cardiotoxic, main concern

Acute: Arrhythmias, ECG change
Chronic: Cardiomyopathy, CHF
Delayed: Cardiomyopathy, CHF

54
Q

Risk factors for cardiomyopathy/CHF

A

cumulative dose, drugs have max lifetime dose
prior cardiac disease…High BP, diabetes
prior radiation therapy or with other cardiotoxic drugs
< 3, and > 70

55
Q

Prevention of Cardiomyopathy

A

Monitor ejection fraction

Monitor cumulative doses

Dexrazoxane (Zinecard), chelates free Fe, IV 10 times chemo dose. given when receive doxorubicin

56
Q

Mitomycin

A

MOA: alkylation of DNA
IV admin
Hepatic metabolism and renal elimination, half life = 50min
delayed marrow suppression

57
Q

Bleomycin

A

MOA:Cuts DNA, fragmenting into pieces

Can be given IV,IM,SQ

elimination renal

Distribution skin/lungs

Bleomycin hydrolase metabolizes drug, and this enzyme is deficient in skin and lungs

58
Q

Bleomycin adverse effects

A

NOT myelosuppressive

Little nausea/vomiting

Hair thinning

skin toxicities

cumulative pulmonary damage

59
Q

Incidence of bleomycin pneumonitis

A

dose related and cumulative

~ 5 -10%

60
Q

Bleomycin Pulmonary

A

causes pulmonary fibrosis

max dose is 450mg

Risks:
lifetime dose
> 70 age
prior pulmonary disease/ radiation therapy
Oxygen admin
61
Q

3 classes of antimetabolites

A

Pyrimidine analogs
Folic Acid analogs
Purine Analogs

62
Q

Methotrexate MOA

A

Inhibits enzyme dihydrofolate reductase

63
Q

Methotrexate Pharmacokinetics Absorption

A

Carrier mediated active transport system in gut if given PO, cancer doses too high but ok for RA doses

almost complete absorption at low doses

absorbed into systemic circulation after IT admin

64
Q

Methotrexate Pharmacokinetics Distribution

A

good distribution into skin after systemic admin

poor CNS pen at standard dose, good at high dose

Can use Ommaya reservoir

3rd space distribution, don’t give to patient with ascites since it will prolong duration of drug in blood

65
Q

Methotrexate Pharmacokinetics Metabolism

A

Mostly metabolized by kidney, some by liver

liver cant handle getting drug every day, ie better take. at once then 6 over 6 days.

66
Q

Methotrexate Pharmacokinetics Adverse effects

A

Myelosuppression

GI

mucositis - inflammation in mouth (cancer patient doses)

Hepatotoxicity, more common with chronic oral admin….can lower dose if LFTs increased

Neurotoxicity; uncommon systemic admin, most common IT

Pulmonary damage; days-years and total dose 40-6,500 mg

67
Q

Methotrexate IV admin

A

25-75 mg/m2

68
Q

Methotrexate IT dose

A

6-12 mg/m2 max 15 mg 1-2/week

69
Q

Methotrexate High dose therapy

A

Protocol dependent
usually in grams per m2

potentially fatal doses, leucovorin used to prevent that

70
Q

Methotrexate oral therapy

A

Psoriasis/RA

2.5-5 mg Q12h/3 doses per week
or 7.5/15 mg once a week

71
Q

Pemetrexed MOA

A

Folic Acid Analog

Inhibition of Thymidylate synthase, DHFR and GARFT

works on folate dependent enzymes, which make purines required for DNA

drug is converted intracellularly

72
Q

Pemetrexed Pharmacokinetics

A

admin by IV
renal elimination

pt has to be pretreated with folic acid and vitamin B12 and receive dexamethasone

NSAIDs issue with this drug

73
Q

Premetrexed adverse effects

A

myelosuppression
cutaneous reactions
GI toxicity
fatigue

74
Q

Purine analogs

A

6-mercaptopurine

6-thioguanine

75
Q

Mercaptopurine metabolism….

A

xanthine oxidase

interaction with allopurinol, want to avoid using but if have to then reduce mercaptopurine dose by 75%

76
Q

Thioguanine metabolism….

A

guanase

77
Q

Pyrimidine analogs

A

5-Fluorouracil
Capecitabine
Gemcitabine
Cytarabine

78
Q

5-Fluorouracil

A

Metabolite 5FdUMP halts DNA synthesis

79
Q

5FU + Leucovorin

A

Leucovorin will supply the reduced folate thats necessary, potentiating effected of 5FU

Keeps 5FU and TS together longer

80
Q

5FU absorption

A

can be given orally, but as another product that gets metabolized to 5FU

Topical admin too

81
Q

5FU Distribution

A

well distributed
some CNS penetration
does get into third spaces

82
Q

5FU metabolism

A

elimination in renal and liver, short half life

83
Q

5FU Adverse effects

A 
Myelosuppression
nausea/vomiting
Mucositis - dose related
Diarrhea (essentially mucositis in colon)
some hairless, nail changes

Hand and food syndrome inflammation palms and soles of feet

Neurological (acute cerebellar syndrome) = rare
Opthalmic - excessive lacrimation

occasional cardiac effects

DI with warfarin

84
Q

Capecitabine (Xeloda)

A

Pro drug, metabolized to 5FU

oral version 5FU

85
Q

Capecitabine Pharmacokinetics

A

Absorbed well orally, peak levels in about 2 hrs

Metabolized in liver and tissues

DI with warfarin

86
Q

Capecitabine Adverse effects

A

Nausea/vomiting
Diarrhea - 55%
Hand and foot syndrome - 55%, 15-20% severe
LFT elevations

due to frequency of admin

Myelosuppresion
Neurotoxicity
Cardiac toxicity

87
Q

Capecitabine dosing

A

1,250 mg/m2 PO q12h for 2 weeks, 1 week rest
take within 30min after meal

can reduce to 850-1,000 mg/m2 q12hr to reduce toxicity, lowest you can go

dose adjustments based on renal functions

88
Q

4 classes of natural products

A

Vinca alkaloids
Epipodophylotoxins
Taxanes
Camptothecin derivatives

89
Q

Vinca alkaloids MOA

A

prevents assembly aspect of microtubules, disassembly dominates

90
Q

Vinca alkaloids Pharmacokinetics

A

absorption: IV only, IM pain/harmful
Distribution: well distributed except for CNS
Eliminated by liver, some in urine

Vincristine longest gamma half life, also most neurons toxic

91
Q

Dose limiting side effects for Vinlastine and Vinorelbine?

A

Myelosuppression

92
Q

Neurotoxicity of Vinca Alkaloids

A 
Vincrisitne = dose limiting
Vinblastine = less common than vincristine
Vinorelbine = up to 30%
93
Q

Vincristine Neurotoxicity

A

dose related and cumulative
Peripheral neuropathy, reflex first to go
Autonomic dysfunction

Onset: gradually after 3-4 doses
usually reversible with discontinuation
management: stop the drug

94
Q

Why is vincristine recommended to be dispensed in a mini bag, not syringe?

A

to prevent inadvertent intrathecal admin

95
Q

Vinca Alkaloids effects

A

Skin/hair loss and stuff

Constipation

SIADH, Raynauds phenomenon rare

96
Q

Max single dose vincristine?

A

2 mg

97
Q

Epipodophylotoxins

A

Etoposide - most common

Teniposide

98
Q

Etoposide comes from…

A

may apple

99
Q

Etoposide MOA

A

cuts strand of DNA
inhibit topoisomerase II
Most active in S and G2 phase

100
Q

Etoposide Pharmacokinetics

A

Absorption: IV and PO
bioavailability is 50% po

Distribution is about 0-10% cns
Metabolized by liver

101
Q

Etoposide adverse effects

A 
Myleosuppression
GI = Nausea/vomiting, mucositis
hair loss, local tissue damage
** Hypotension ** infusion no less then 30 min
Radiation recall and neuropathy
102
Q

Etoposide Admin

A

oral dose is twice the IV dose

best activity given over 3-5 days

103
Q

Docetaxel soruce

A

English yew

104
Q

Paclitaxel source

A

Pacific yew

105
Q

Cabazitaxel source

A

European yew

106
Q

Taxane MOA:

A

Microtubule stabilization

bind to microtubules and prevent depolymerization

107
Q

Taxanes pharmacokinetics

A

given IV only

hepatic metabolism

108
Q

Taxane Adverse effects

A

Hypersensitivity

Rash, hypotension

can get anaphylaxis

109
Q

Taxane with highest hypersensitivity

A

Paclitaxel, 31-45%

110
Q

Paclitaxel Hypersensitivity prevention

A

corticosteroid, antihistamine, H2 blocker

111
Q

Albumin-bound paclitaxel hypersensitivity prevention

A

not usually necessary

112
Q

Docetaxel

A

oral corticosteroid before, day of, after treatmetn

also prevents fluid retention

113
Q

Cabazitaxel

A

corticosteroid, antihistamine and H2 blocker

114
Q

Paclitaxel Adverse effects

A

Hypotension
Myelosuppression
Neurotoxicity

115
Q

Difference between albumin and regular paclitaxel

A

regular is solubilized in cremophor, might cause hypersensivity

Albumin bound is bound to albumin

116
Q

Advantages of Nab-paclitaxel (Albumin bound)

A

solvent free

deliver higher dose in shorter infusion

no need for premed to prevent hypersensitivity

117
Q

Albumin-bound paclitaxel important info

A

when given in combo, sequence important

should be given before carboplatin or gemcitabine

118
Q

Docetaxel

A

major side effect is fluid retention, in about ~50%

onset cumulative dose of > 400%

119
Q

Cabazitaxel

A

Hypersensitivity reactions w/I first few min

all patients must be premeditated 1/2 hr before

Gi - nausea,vomiting, diarrhea
Neutropenia
marrow suppresion

120
Q

Cabazitaxel admin

A

given in combo with oral prednisone throughout treatment

25mg/m2 every 3 weeks as 1hr infusion

in-line filter of 0.22 micrometer

121
Q

Captothecin derivatives MOA:

A

inhibit topoisomerase I

122
Q

Topotecan

A

can be given IV or PO, 40% bioavail

Metabolized by Liver

123
Q

Irinotecan

A

has active metabolite SN 38

124
Q

Topotecan Adverse effects

A

marrow suppressive

Nausea, vomiting, diarrhea, constipation, stomatitis

125
Q

Irinotecan Adverse effects

A

Marrow suppressive

nausea,vomiting,diarrhea

126
Q

Irinotecan-associated diarrhea

A

onset w/I 24hr of admin

Cholinergic syndorme, managed with atropine

Delayed onset > 24hrs (80-90%)
Managed with loperamide

Pharmacology & Medical Chemistry II (43 decks)

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