Exam 3: Lecture 1,2,3 Pharmacology of Cancer Drugs Flashcards
What is cancer?
Disease characterized by uncontrolled proliferation of abnormal cells.
Growth Characteristics of the malignant cell?
Genetic change
Uncontrolled proliferation
Invasiveness
Metastasis
G0 phase….
cell does not actively divide, doing whatever it does
How will cell go from G0 to G1?
gets signal
S phase…
Synthesis
G2 phase….
prepare for mitosis
M phase….
Mitosis occurs
1 cell differentiates to perform predetermined function
1 cell is able to divide if it gets stimulus
What makes cancer cells different?
2 new cells will retain ability to divide and they will proliferate without stimulus…leading to increase in cell mass
Classes of antineoplastic
Chemotherapy
Hormones
Targeted therapy
Classes of chemotherapy
Alkylating agents antibiotics Antimetabolites Natural products Miscellaneous agents
Classes of Targeted therapy?
Monoclonal antibodies
Tyrosine Kinase inhibitors
Many others
MOA Alkylators
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
Cyclophosphamide (Cytoxan)
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
Universal side effects fo chemo agents?
Myelosupppression
nausea and vomiting
alopecia
Cyclophosphamide (Cytoxan) adverse effects
Gonadal suppression
Hemorrhagic Cystitis ~15% pt
Cardiotoxicity
+ universal side effects
Myelosuppression
WBC will drop, hit nadir and then recover
recover occurs around 3rd week, which is why regimens are given every 3 weeks
Nadir is…
time of maximal bone marrow suppression
usually around day 8-10
cells affected by Myelosuppression…
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
Ifosfamide
sister drug for Cyclophosphamide
Ifosfamide Pharmacokinetics
Only given IV
Crosses placenta/milk
Hepatic activation to active and toxic metabolites
half life = 6 hrs
much slower activation than cyclophosphamide, dose higher
Ifosfamide Adverse effects
CNS toxicity, crosses BBB
Hemorragic cystitis much more common ~50%+
Hemorrhagic cystitis
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
Hemorrhagic cystitis prevention
lots of hydration, drink a lot of water
MESNA
MESNA
dimerized in urine, binds to acrolein and inactivates it so it cant effect bladder wall and prevent development of Hemorrhagic Cystitis
3 Nitrosoureas…
Carmustine
Lomustine
Streptozocin
Lomustine available only in….
tablet (PO) form
Carmustine available in….
Iv and Wafers (insertion into brain)
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
Nitrosourea adverse effects
SEVERE nausea and vomiting
Delayed mylosuppression***, true nadir around week 4
Alopecia
Chronic Nephrotoxicity and Pulmonary toxicity
How often nitrosourea given?
every 6 weeks due to mylosuppression
Platinum-based agents
Cispaltin
Carboplatin
Oxaliplatin
Cisplatin Pharmacokinetics
Mostly given IV
Eliminated renally
All Platins are excreted through….
The urine
have to be mindful of patients kidney situation for dose
“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
Cisplatin Nephrotoxicity
Acute renal failure
Dose related and cumulative
Risks: Dehydration, other nephrotoxic drugs
Electrolyte disorders with Platins….
Mostly effect Potassium and Magnesium, decrease all
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
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
cisplatin Ototoxicity
high frequency hearing loss
dose related, cumulative, maybe irreversible
uncommon with other platins
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
Carboplatin Regimin
360 mg/m2 every 4 weeks alone
300 mg/m2 every 4 weeks with CTX
no need for hydration
Taxane first
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
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***
Temozolamide
Given IV or PO
Degrades to MTIC
Good penetration across BBB….brain tumors
Doxorubicin family MOA
Drug binds to DNA through intercalation
Topoisomerase II inhibition, can cut but not glue
form free radicals, except mitoxantrone
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
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)
color that mitoxantrone will make pee?
blue or greenish
doxorubicin family Adverse effects
Myelosuppression
GI stuff
Hairloss, entire body
Hyperpigmentation and local tissue damage
Extravasation
leaking out of vein into tissue
given by slow push to avoid it
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
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
All drugs in Doxorubicin family are….
cardiotoxic, main concern
Acute: Arrhythmias, ECG change
Chronic: Cardiomyopathy, CHF
Delayed: Cardiomyopathy, CHF
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
Prevention of Cardiomyopathy
Monitor ejection fraction
Monitor cumulative doses
Dexrazoxane (Zinecard), chelates free Fe, IV 10 times chemo dose. given when receive doxorubicin
Mitomycin
MOA: alkylation of DNA
IV admin
Hepatic metabolism and renal elimination, half life = 50min
delayed marrow suppression
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
Bleomycin adverse effects
NOT myelosuppressive
Little nausea/vomiting
Hair thinning
skin toxicities
cumulative pulmonary damage
Incidence of bleomycin pneumonitis
dose related and cumulative
~ 5 -10%
Bleomycin Pulmonary
causes pulmonary fibrosis
max dose is 450mg
Risks: lifetime dose > 70 age prior pulmonary disease/ radiation therapy Oxygen admin
3 classes of antimetabolites
Pyrimidine analogs
Folic Acid analogs
Purine Analogs
Methotrexate MOA
Inhibits enzyme dihydrofolate reductase
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
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
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.
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
Methotrexate IV admin
25-75 mg/m2
Methotrexate IT dose
6-12 mg/m2 max 15 mg 1-2/week
Methotrexate High dose therapy
Protocol dependent
usually in grams per m2
potentially fatal doses, leucovorin used to prevent that
Methotrexate oral therapy
Psoriasis/RA
2.5-5 mg Q12h/3 doses per week
or 7.5/15 mg once a week
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
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
Premetrexed adverse effects
myelosuppression
cutaneous reactions
GI toxicity
fatigue
Purine analogs
6-mercaptopurine
6-thioguanine
Mercaptopurine metabolism….
xanthine oxidase
interaction with allopurinol, want to avoid using but if have to then reduce mercaptopurine dose by 75%
Thioguanine metabolism….
guanase
Pyrimidine analogs
5-Fluorouracil
Capecitabine
Gemcitabine
Cytarabine
5-Fluorouracil
Metabolite 5FdUMP halts DNA synthesis
5FU + Leucovorin
Leucovorin will supply the reduced folate thats necessary, potentiating effected of 5FU
Keeps 5FU and TS together longer
5FU absorption
can be given orally, but as another product that gets metabolized to 5FU
Topical admin too
5FU Distribution
well distributed
some CNS penetration
does get into third spaces
5FU metabolism
elimination in renal and liver, short half life
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
Capecitabine (Xeloda)
Pro drug, metabolized to 5FU
oral version 5FU
Capecitabine Pharmacokinetics
Absorbed well orally, peak levels in about 2 hrs
Metabolized in liver and tissues
DI with warfarin
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
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
4 classes of natural products
Vinca alkaloids
Epipodophylotoxins
Taxanes
Camptothecin derivatives
Vinca alkaloids MOA
prevents assembly aspect of microtubules, disassembly dominates
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
Dose limiting side effects for Vinlastine and Vinorelbine?
Myelosuppression
Neurotoxicity of Vinca Alkaloids
Vincrisitne = dose limiting Vinblastine = less common than vincristine Vinorelbine = up to 30%
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
Why is vincristine recommended to be dispensed in a mini bag, not syringe?
to prevent inadvertent intrathecal admin
Vinca Alkaloids effects
Skin/hair loss and stuff
Constipation
SIADH, Raynauds phenomenon rare
Max single dose vincristine?
2 mg
Epipodophylotoxins
Etoposide - most common
Teniposide
Etoposide comes from…
may apple
Etoposide MOA
cuts strand of DNA
inhibit topoisomerase II
Most active in S and G2 phase
Etoposide Pharmacokinetics
Absorption: IV and PO
bioavailability is 50% po
Distribution is about 0-10% cns
Metabolized by liver
Etoposide adverse effects
Myleosuppression GI = Nausea/vomiting, mucositis hair loss, local tissue damage ** Hypotension ** infusion no less then 30 min Radiation recall and neuropathy
Etoposide Admin
oral dose is twice the IV dose
best activity given over 3-5 days
Docetaxel soruce
English yew
Paclitaxel source
Pacific yew
Cabazitaxel source
European yew
Taxane MOA:
Microtubule stabilization
bind to microtubules and prevent depolymerization
Taxanes pharmacokinetics
given IV only
hepatic metabolism
Taxane Adverse effects
Hypersensitivity
Rash, hypotension
can get anaphylaxis
Taxane with highest hypersensitivity
Paclitaxel, 31-45%
Paclitaxel Hypersensitivity prevention
corticosteroid, antihistamine, H2 blocker
Albumin-bound paclitaxel hypersensitivity prevention
not usually necessary
Docetaxel
oral corticosteroid before, day of, after treatmetn
also prevents fluid retention
Cabazitaxel
corticosteroid, antihistamine and H2 blocker
Paclitaxel Adverse effects
Hypotension
Myelosuppression
Neurotoxicity
Difference between albumin and regular paclitaxel
regular is solubilized in cremophor, might cause hypersensivity
Albumin bound is bound to albumin
Advantages of Nab-paclitaxel (Albumin bound)
solvent free
deliver higher dose in shorter infusion
no need for premed to prevent hypersensitivity
Albumin-bound paclitaxel important info
when given in combo, sequence important
should be given before carboplatin or gemcitabine
Docetaxel
major side effect is fluid retention, in about ~50%
onset cumulative dose of > 400%
Cabazitaxel
Hypersensitivity reactions w/I first few min
all patients must be premeditated 1/2 hr before
Gi - nausea,vomiting, diarrhea
Neutropenia
marrow suppresion
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
Captothecin derivatives MOA:
inhibit topoisomerase I
Topotecan
can be given IV or PO, 40% bioavail
Metabolized by Liver
Irinotecan
has active metabolite SN 38
Topotecan Adverse effects
marrow suppressive
Nausea, vomiting, diarrhea, constipation, stomatitis
Irinotecan Adverse effects
Marrow suppressive
nausea,vomiting,diarrhea
Irinotecan-associated diarrhea
onset w/I 24hr of admin
Cholinergic syndorme, managed with atropine
Delayed onset > 24hrs (80-90%)
Managed with loperamide
