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

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
3 Nitrosoureas...
Carmustine Lomustine Streptozocin
26
Lomustine available only in....
tablet (PO) form
27
Carmustine available in....
Iv and Wafers (insertion into brain)
28
Pharmacokinetics of Carmustine & Lomustine
Carmoustine - systemic absorb of wafers uneval Lomustine - rapidly absorb after PO admin Distribution: Cross BBB, distribute into milk Active hepatic metabolism and urinary elimination
29
Nitrosourea adverse effects
SEVERE nausea and vomiting Delayed mylosuppression***, true nadir around week 4 Alopecia Chronic Nephrotoxicity and Pulmonary toxicity
30
How often nitrosourea given?
every 6 weeks due to mylosuppression
31
Platinum-based agents
Cispaltin Carboplatin Oxaliplatin
32
Cisplatin Pharmacokinetics
Mostly given IV Eliminated renally
33
All Platins are excreted through....
The urine have to be mindful of patients kidney situation for dose
34
"Platinum" Adverse effects
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
35
Cisplatin Nephrotoxicity
Acute renal failure Dose related and cumulative Risks: Dehydration, other nephrotoxic drugs
36
Electrolyte disorders with Platins....
Mostly effect Potassium and Magnesium, decrease all
37
Cisplatin Neurotoxicity
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
38
Oxaliplatin neurotoxicity
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
39
cisplatin Ototoxicity
high frequency hearing loss dose related, cumulative, maybe irreversible uncommon with other platins
40
Cisplatin Regimin
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
41
Carboplatin Regimin
360 mg/m2 every 4 weeks alone 300 mg/m2 every 4 weeks with CTX no need for hydration Taxane first
42
Calvert Formula
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
43
cautions with Platin
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***
44
Temozolamide
Given IV or PO Degrades to MTIC Good penetration across BBB....brain tumors
45
Doxorubicin family MOA
Drug binds to DNA through intercalation Topoisomerase II inhibition, can cut but not glue form free radicals, except mitoxantrone
46
What does Topoisomerase do?
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
47
Doxorubicin family Pharmacokinetics
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)
48
color that mitoxantrone will make pee?
blue or greenish
49
doxorubicin family Adverse effects
Myelosuppression GI stuff Hairloss, entire body Hyperpigmentation and local tissue damage
50
Extravasation
leaking out of vein into tissue given by slow push to avoid it
51
Prevention and management of extravasation
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
Radiation recall
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
All drugs in Doxorubicin family are....
cardiotoxic, main concern Acute: Arrhythmias, ECG change Chronic: Cardiomyopathy, CHF Delayed: Cardiomyopathy, CHF
54
Risk factors for cardiomyopathy/CHF
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
Prevention of Cardiomyopathy
Monitor ejection fraction Monitor cumulative doses Dexrazoxane (Zinecard), chelates free Fe, IV 10 times chemo dose. given when receive doxorubicin
56
Mitomycin
MOA: alkylation of DNA IV admin Hepatic metabolism and renal elimination, half life = 50min delayed marrow suppression
57
Bleomycin
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
Bleomycin adverse effects
NOT myelosuppressive Little nausea/vomiting Hair thinning skin toxicities cumulative pulmonary damage
59
Incidence of bleomycin pneumonitis
dose related and cumulative ~ 5 -10%
60
Bleomycin Pulmonary
causes pulmonary fibrosis max dose is 450mg ``` Risks: lifetime dose > 70 age prior pulmonary disease/ radiation therapy Oxygen admin ```
61
3 classes of antimetabolites
Pyrimidine analogs Folic Acid analogs Purine Analogs
62
Methotrexate MOA
Inhibits enzyme dihydrofolate reductase
63
Methotrexate Pharmacokinetics Absorption
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
Methotrexate Pharmacokinetics Distribution
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
Methotrexate Pharmacokinetics Metabolism
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
Methotrexate Pharmacokinetics Adverse effects
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
Methotrexate IV admin
25-75 mg/m2
68
Methotrexate IT dose
6-12 mg/m2 max 15 mg 1-2/week
69
Methotrexate High dose therapy
Protocol dependent usually in grams per m2 potentially fatal doses, leucovorin used to prevent that
70
Methotrexate oral therapy
Psoriasis/RA 2.5-5 mg Q12h/3 doses per week or 7.5/15 mg once a week
71
Pemetrexed MOA
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
Pemetrexed Pharmacokinetics
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
Premetrexed adverse effects
myelosuppression cutaneous reactions GI toxicity fatigue
74
Purine analogs
6-mercaptopurine | 6-thioguanine
75
Mercaptopurine metabolism....
xanthine oxidase interaction with allopurinol, want to avoid using but if have to then reduce mercaptopurine dose by 75%
76
Thioguanine metabolism....
guanase
77
Pyrimidine analogs
5-Fluorouracil Capecitabine Gemcitabine Cytarabine
78
5-Fluorouracil
Metabolite 5FdUMP halts DNA synthesis
79
5FU + Leucovorin
Leucovorin will supply the reduced folate thats necessary, potentiating effected of 5FU Keeps 5FU and TS together longer
80
5FU absorption
can be given orally, but as another product that gets metabolized to 5FU Topical admin too
81
5FU Distribution
well distributed some CNS penetration does get into third spaces
82
5FU metabolism
elimination in renal and liver, short half life
83
5FU Adverse effects
``` 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
Capecitabine (Xeloda)
Pro drug, metabolized to 5FU oral version 5FU
85
Capecitabine Pharmacokinetics
Absorbed well orally, peak levels in about 2 hrs Metabolized in liver and tissues DI with warfarin
86
Capecitabine Adverse effects
Nausea/vomiting Diarrhea - 55% Hand and foot syndrome - 55%, 15-20% severe LFT elevations due to frequency of admin Myelosuppresion Neurotoxicity Cardiac toxicity
87
Capecitabine dosing
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
4 classes of natural products
Vinca alkaloids Epipodophylotoxins Taxanes Camptothecin derivatives
89
Vinca alkaloids MOA
prevents assembly aspect of microtubules, disassembly dominates
90
Vinca alkaloids Pharmacokinetics
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
Dose limiting side effects for Vinlastine and Vinorelbine?
Myelosuppression
92
Neurotoxicity of Vinca Alkaloids
``` Vincrisitne = dose limiting Vinblastine = less common than vincristine Vinorelbine = up to 30% ```
93
Vincristine Neurotoxicity
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
Why is vincristine recommended to be dispensed in a mini bag, not syringe?
to prevent inadvertent intrathecal admin
95
Vinca Alkaloids effects
Skin/hair loss and stuff Constipation SIADH, Raynauds phenomenon rare
96
Max single dose vincristine?
2 mg
97
Epipodophylotoxins
Etoposide - most common | Teniposide
98
Etoposide comes from...
may apple
99
Etoposide MOA
cuts strand of DNA inhibit topoisomerase II Most active in S and G2 phase
100
Etoposide Pharmacokinetics
Absorption: IV and PO bioavailability is 50% po Distribution is about 0-10% cns Metabolized by liver
101
Etoposide adverse effects
``` Myleosuppression GI = Nausea/vomiting, mucositis hair loss, local tissue damage ** Hypotension ** infusion no less then 30 min Radiation recall and neuropathy ```
102
Etoposide Admin
oral dose is twice the IV dose best activity given over 3-5 days
103
Docetaxel soruce
English yew
104
Paclitaxel source
Pacific yew
105
Cabazitaxel source
European yew
106
Taxane MOA:
Microtubule stabilization bind to microtubules and prevent depolymerization
107
Taxanes pharmacokinetics
given IV only | hepatic metabolism
108
Taxane Adverse effects
Hypersensitivity Rash, hypotension can get anaphylaxis
109
Taxane with highest hypersensitivity
Paclitaxel, 31-45%
110
Paclitaxel Hypersensitivity prevention
corticosteroid, antihistamine, H2 blocker
111
Albumin-bound paclitaxel hypersensitivity prevention
not usually necessary
112
Docetaxel
oral corticosteroid before, day of, after treatmetn also prevents fluid retention
113
Cabazitaxel
corticosteroid, antihistamine and H2 blocker
114
Paclitaxel Adverse effects
Hypotension Myelosuppression Neurotoxicity
115
Difference between albumin and regular paclitaxel
regular is solubilized in cremophor, might cause hypersensivity Albumin bound is bound to albumin
116
Advantages of Nab-paclitaxel (Albumin bound)
solvent free deliver higher dose in shorter infusion no need for premed to prevent hypersensitivity
117
Albumin-bound paclitaxel important info
when given in combo, sequence important should be given before carboplatin or gemcitabine
118
Docetaxel
major side effect is fluid retention, in about ~50% onset cumulative dose of > 400%
119
Cabazitaxel
Hypersensitivity reactions w/I first few min all patients must be premeditated 1/2 hr before Gi - nausea,vomiting, diarrhea Neutropenia marrow suppresion
120
Cabazitaxel admin
given in combo with oral prednisone throughout treatment 25mg/m2 every 3 weeks as 1hr infusion in-line filter of 0.22 micrometer
121
Captothecin derivatives MOA:
inhibit topoisomerase I
122
Topotecan
can be given IV or PO, 40% bioavail Metabolized by Liver
123
Irinotecan
has active metabolite SN 38
124
Topotecan Adverse effects
marrow suppressive | Nausea, vomiting, diarrhea, constipation, stomatitis
125
Irinotecan Adverse effects
Marrow suppressive | nausea,vomiting,diarrhea
126
Irinotecan-associated diarrhea
onset w/I 24hr of admin Cholinergic syndorme, managed with atropine Delayed onset > 24hrs (80-90%) Managed with loperamide