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chemotherapy pharmacology

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K R

on 20 November 2012

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Transcript of chemotherapy pharmacology

chemotherapy
pharmacology alkylating agents antimetabolites antimicrotubules topoisomerase inhibitors antitumor antibiotics general characteristics non-phase specific
-cytotoxic throughout cell cycle
-cell kill proportional to dose cell cycle specific
-cell kill proportional to the
number of cells in that phase
of the cycle agents
(6) nitrogen
mustards
(5) methylhydrazine
derivative
(1) alkyl
solfonate
(1) nitrosources
(not commonly used
but crosses BBB)
(4) triazines
(2) platinums
(3) mechlorethamine
cyclophosphamide
ifosfamide
melphalan
chlorambucil procarbazine busulfan carmustine
lomustine
streptozocin
bendamustine dacarbazine
temozolomide cisplatin
carboplatin
oxaliplatin MOA general
common
toxicity unique
toxicities the net effect of alkylating agents is achieved by
misreading of DNA code by
cross-linking of DNA which prevents cellular division so can't divide ( and get misreading of code)
single or double stranded DNA breaks
any of these -> inhibition of DNA, RNA or protein synthesis n/v mostly acute, some delayed most moderate (MEC) [30-90%]
which ones are HIGH(HEC)?
ther are 3 which ones are delayed emesis?
(delayed = days after chemo) HIGH=
cisplatin
nitrosureas
decarbazine cisplatin myelosuppression (usually recover from myelosuppression w/in month) which alkyating agent has
delayed myelosuppression? nitrosoureas
carmustine
lomustine
streptozocin
bendamustine (usually see 6-8 wks after
admin of drug) vesicants name 3 mechlorethamine
melphalan
oxaliplatin other name 4 other common toxicities mucositits
alopecia
sterility/infertility
secondary malignancies platinums:
N/V
nephrotoxicity
neurotoxicity
myelosuppression
radiosensitizer which are worse for which? Nausea/vomiting XX x x
Nephrotoxicity X x
Neurotoxicity X X
Myelosuppression x X x
Radiosensitizer XX csiplatin carboplatin oxaliplatin oxaliplatin neurtotoxicitis name two kinds 1)peripheral neurotoxicity (68%)
acute: (primary peripheral neuropathy)
-occurs within 1-2 days and is reversible lasts ~14 days and is exacerbated by the cold (so don't handle cold things and it will help minimize the neuropahty)
chronic: lasts >14 days, interferes with ADL and may improve upon discontinuation
2)pharyngolaryngeal dysethesia
rare(<1%)
feels like you are choking but you aren't
occurs with cold busulfan pulmonary
venoocclusive disease
skin pigmentation
seizures (high doses) agents
(4) folic acid analogs
(2) methotrexate
pemetrexed pyrimidine analogs
(5) 5-flurouracil, capecitabine
cytarabine
gemcitabine
5-azacytidine
decitabine purine analogs
(4)
pentostatin
fludarabine
clofarabine
nercaptopurine MOA general
common
toxicities unique
toxicities cyclophosphamide
and
Ifosfamide these drugs are similar, so similar ADR. what are their toxicities and what considerations do you have to take into effect DRUG TOXICITY CONSIDERATIONS
___________________________________________________________
cylophosphamide hemorrhagic cystitis -->fluid +/- mensa
SIADH -->monitor Na levels
cardiomyopathy (high dose)-->monitor
ifosfamide hemorrhagic cystitis -->fluid +/- mensa
SIADH -->monitor Na levels
encephalopathy -->monitor, methylene blue
renal -->monitor (SCr, BUN) pt needs to be able to tolerate fluids before going home S-phase specific interferes with normal synthesis of nucleic acids in different ways:
substitute for purines or pyrimidines
inhibit NZ involved in mucleic acid synthesis
cause decrease DNA, RNA and protein synthesis and therefore causes decreased cellular replication Leucovorin and
5-FU and Methotrexate 1)5-FU [often used to tx colon CA]works by inhibiting the conversion of uridine to thymadine by inhibiting the NZ thymidylate synthase (this NZ is needed for DNA replication) and since it is blocked you get no DNA synthesis
2)Leucovirin (AKA reduced folate) enhances the bond between 5-FU and thymidylate synthase and therefore increases toxicity of 5-FU and can give less 5-FU to pt, but the cellular toxicity is enhanced
3)methotrexate inhibits the NZ DHFR and preventst the coversion of folic acid into reduced folate (leucovorin)
[Reduced folate is needed for DNA synthesis to occur, so methotrexate prevents regular folic acid to go to reduced folate so when give methotrexate to a pt and you also give leucovorin with methotrexate, leucovorin is preferentially taken up by normal cells so we are able to rescue normal cells over the tumor cells and when methotrexate is given in high doses we can give leucovorin to prevent the side effects of methotrexate] 1) 2) 3) myelosuppression tell me about
methotrexate
gemcitabine
mercaptopurine and thioguanine methotrexate: acculumates in fluid collections (slow efflux leads to prolonged activity) [so don't give to pt's with a lot of fluid or ascities Gemcitabine: greater myelosuppression wih longer infusions [so try to limit infusion time] Mercaptopurine & Thioguanine: are lymphotoxic N/V usually mild but what causes moderate to severe emesis? high dose cytarabine
high dose methotrexate other mucositis
skin and nail changes (2) methotrexate Pemetrexed 5-FU
&
Capecitabine DRUG TOXICITY CONSIDERATIONS
______________________________________________________
methotrexate nephrotoxicity * fluid w/ bicarb**, avoid DDI***
hepatic monitor
pulmonary monito * esp. with high doses
** eliminates methotrexate in urine
*** acidic drugs, foods DRUG TOXICITY CONSIDERATIONS
______________________________________________________
Pemetrexed rash dexamethasone
neutropenic sepsis B12 and folate supplementation DRUG TOXICITY CONSIDERATIONS
_________________________________________________________________
5-FU cardiac toxicity monitor
infusion: hand foot syndrome
bolus: diarrhea
mucositis
myelosuppression
Capecitabine* diarrgea
hand foot syndrome**
myelosuppression * is the oral form of 5-FU
** palms of feet get sweaty so no running and keep temp down, no hot showers agents
(4) vina
alkaloids
(3) taxanes
(3) epolithilones
(1) miscellaneous
(1) vinblastine
vinorelbine
vincristine paclitaxel
docetaxel
cabazitaxel Ixabepilone (used in met. breast CA) eribulin MOA antimicotubules toxicities:
myelosuppression
peripheral neurophathy
HSN
Constipation
Neurotoxicity
Vesicant
Fluid retention VNC VNB,ERI PAC,CAB DOC IXA
myelosuppression X X X X
peri. neuropathy XX X XX X XX
hyper sens rxn XX X XX
constipation * XX X
neurotoxicity X X
vesicant *** X X
fluid retention ** XX VCN: vincristine VBN: vinblastine ERI: eribulin PAC: paclitaxel
CAB: cabazitaxel DOC: docetaxel IXA: ixabepilone *want to make sure pt has a BM before giving
** pt get dexamethasome to prevent this
*** get severe tissue damage is it leaks out of IV neurotoxicity peripheral neuropathy (4 types, some overlap) hypersensitivity rxn Peripheral Neuropathy
numbness, paresthesia, pain in hands and feet
bortezmib, platinums, taxanes, thalidomide, vincas
Autonomic Toxicity
constipation, paralytic ileus, urinary retention, incontinence
vincas, cisplatin
Other
encephalopathy
confusion
unsteady gait
seizures
ototoxicity
Fatigue prevention treatment typically senseory paresthesias, dysesthesias, hypoesthesias
interferes with ADL
dose related
may reverse on discontinuation avoid concurrent neurotoxins
monitor cumulative dose
avoid in pts with pre-existing neuropathy stop/ reduce dose of chemotherapy
treat neuropathic pain
-antidepressants (amitriptyline, venlafaxine, SSRI)
-anticonvulsants (gabapentin)
-pregabalin fatigue what relieves it and what doesn't Near universal side effect, NOT relieved by rest or sleep
Management
help pt with set realistic goal for activity, rest/ sleep
emphazise good nutrition
check med profile for OTC or other drugs that may exacerbate problem
stress improtance of 20-30 min of excersize per day
amphetamines, modafinil what are the signs and symptoms and when do
they occur Paclitaxel/
Cremophor EL Prevention
w/.... Management paclitaxel/
cabazitaxel docetaxel Ixabepilone diphenhydramine
rantidine dexamethasone diphenhydramine [H1]
rantidine [H2]
dexamethasone (overal suppression of immune system) usually occurs within 5-10 min of starting the first infusion
s/s
dyspnea
urticaria
angioedema
rash
bronchospasm
hypotension
chest, back and abd cramping mechansism: not compeltely understood, non-immunologically mediated release of histamine like substances dose?
rate? Dose: ? decreased incidnce with smaller weekly doses
Rate: no difference between 3 and 24 hour infusion schedules with premedication mild moderate severe mild flushing, rash, itching
administer additional steroid, benadryl
closely monitor
(ok to keep treating) moderate rash, mild dyspnea, CP, HoTN


administer benadryl/steroids
restart at lower rate and slowly increase severe bronchospasm, HoTN, SOB


benadryl, steroid
epinephrine or bronchodilators prn
IV fluids these drugs work in the M-phase
-microtubules are important structures that are involved in cellular mitosis, what these drugs do is bind to microtubules and either stabilize or setabilize them. the net result or either is accumulation of microtubules and then inhibition of mitosis (hence m-phase) toxicities of ...
etoposide
topotecan
irinotecan Irinotecan Induced Diarrhea

genetic component
early onset
late onset hematologic toxicity neutropenia neutropenic precautions thrombocytopenia MOA agents
(2) epipodophyllotoxins
(2) camptothecins
(2) etoposides
teniposide topotecan
irinotecan topoisomerase inhibitors work by inhibiting topoisomerase I or II, they are NZ responsibel to clip DNA to allow it to unwind and replicate and by inhbiting it there is a decrease in DNA replication and then there is cell death etoposide:
HoTN-infuse over 60 minutes, hold antihypertensives (on day of tx)
myelosuppression, alopecia, stomatitis, diarrhea topotecan:
myelosuppression, alopecia, n/v, mucositis irinotecan:
diarrhea, myelosuppression (dose limiting) (dose limiting) genetic genetic variation (in pt's with the amount of) UGT 1A1 (metabolic NZ) that causes increased levels of SN-38 (active metabolite)
test available for UGT 1A1*28 allele early onset early onset (cholinergic syndrome)
transient, may arise up to 24 hours after treatment
sympotoms: profound warmth, rhinitis, lacrimation, salivation, diaphoresis or flushing
abd cramping and sudden diarrhea
management: atroine 0.25-1.0mg IV or SC late onset late onset (>24 hours, median 5-11 days)
dehydration or electrolyte imbalances, can be life-threatening
secretory process secondary to cytotoxic effect on GI mucosa
management: loperamide 4mg PO at first onset then 2 mg PO q 2 hours until diarrhea free x 12 hours
night: loperamide 4mg q 4 hours
DNE: 48 consecutive hours due to to eh risk of paralytic ileus
fluid intake should be maintained to avoid dehydration what's the nadir? myelosuppression
anemia (decease in RBC)
leukopenia (decrease in WBC)
thrombocytompenia (decrease in platelets)

nadir is the lowest count the blood cells fall to, so when a pt is at their nadir, they are at risk for bleeding, infection etc. what would you see on labs to support this? absolute nneutrophil count (ANC) <500 or <1000 with a predicted decline to <500
ANC= WBC x ((segs+bands)/100)
fever is most reliable sign of infections in neutropenic pt becuase they don't have WBC so won't see signs of infiltrates on CXR, no puss and no reness at infection site
source of infection is often not identifies, so if pt is neurtopenic, assume they are infected time course of
neutropenia leukopenia begins on day 7-10
nadir occurs at day 10-14
recovery at 21-28 days
nitrosureas, mitomycin, and mechlorethamine
=delayed neutropenia (6-8wks post drugs)
overall duration:
solid tumor:7-10 days
hematologic malignancy: longer take oral temperature four times each day during expected nadir. call if temp >100.4
wash frequently
eliminate uncooked meats/eggs, was veggies and fruit (depending on degree, may not be able to eat any)
avoid crowds, sick people
hydrate skin, use electric razor
do not clean pet wasate
avoid fresh flowers and plants garden with gloves
avoid enemas, rectal suppositories and rectal temps
no dental work platelet count <10,000/mm3 --> platelet transfusion
thrombocytopenic precuations
avoid IM and perhaps SQ injections (2/2 risk of bleeding)
avoid rectal exams and suppositories
do not schedule routine healthcare visits near time of nadir agents
(2) anthracycline
antibiotics
(4) anthracenedione
(3) daunorubicin
doxorubicin
epirubicin mitoxantrone
bleomycin
mitocmycin C MOA multiple mechanisms of cytotoxicity
intercalates DNA (lrg structure slides into spaces of DNA and prevent replication)
inhibits topoisomerase II ****
forms free radicals common
toxicities myelosuppression (excpet bleomycin[&vincristine])
mucositis/stomatitis
N/V (except bleomycin)
alopecia
vesicant (except bleomycin and mitoxantrone) unique
toxicities bleomycin
(3) anthracyclines
(3) DRUG TOXICITY CONSIDERATIONS
___________________________________________________________
bleomycin pulmonary toxicity risks: renal dysfunction,
chest irratiation, high conc.
of oxygen, cumulative
doses >450 units
skin changes
fever cardiac toxicity DRUG TOXICITY CONSIDERATIONS
___________________________________________________________
anthracyclines cardiac toxicity MUGA scans prior and
periodic, culm doses and
dexrazoxane
radiation recall
red urine (dox) council pt on this mild EKG changes --> CHF
pt risk factors: age>65 or children, radiation to the chest, prior exposure, preexisting cardiac disease, concomitant intensifier
drug specific: cumulative doses, administration, sequence
most common with: antrhacyclines, high dose cyclophosphamides, 5-FU, trastuzumab, paclitaxel basics CINV stomatitis/
mucositis vesicants irritants prevention general CHF avoid in high risk pt's
educate pt on signs of tachycardia, dyspnea, dizziness
educate pt about low salt diet, need for rest periods, to avoid caffeine and alcohol baseline and period LVEF
monitor cumulative dose
give cardioprotectant such as dexrazoxane factors that influence
responses
to chemotherapy
(3) combination chemotherapy ideal regimen should
activity as a single agent in selected in selected disease
agents with a different mechanisms of action
not to be cross resistant
no overlapping doselimiting toxicity (DLT)
act in different phases of the cell cycle
currently no regimens meet all these criteria dose intensity
amount of chemotherap given to a pt over a period of time
determined by dose and schedule
decreased dose intensity yields decrease cure rates
drug resistance
tumor site
patient characteristics chemo terms hematlogic malignancies solid tumors induction try to induce remission consolidation maintenance keep from relapsing years of chemo to maintain remission adjuvent sx or tx after sx; so adjuvent tx is after primary treatment neoadjuvent given before primary tx, ie to shrink tumor before surgery salvage when you exhausted all options terms used in
assessming response complete/partial
remission to be in remission you need:
lack of dz or partial lack of dz
need to recover normal count cure free form dz and same life expectancy than others complete response complete abscense of dz over a period of 1 month partial response increase in measurable dz by 30% over a 1 month period disease progression increase in measurable dz by 20% pt that hasnew tumor when being tx stable disease tumor neither grows or shrins by 20%when getting tx disease free/progression free survival stated as thins because clinical trials don't run long enough overall survival dz free or progression free
(5 yr survival ate is the cure rate) non-pharmacologic therapy prevention agents phases of CINV risk factors
postitive (increases risk of getting n/v
negative (risk factors that protect from n/v four emetic
risk categories Anticipatory emesis:
-Triggered by sights, smells, or sounds, and prior poor control
-Risk factors
-Treatment > 6 months or
highly emetic agents
-h/o anxiety or depression,
poor emetic control
Refractory emesis:
-Not responsive to therapy Acute emesis:
-Occurs within first 24 hours
-Peak: 4-6 hours
Delayed emesis:
- > 24 hours
-Peak: 2-3 days
Breakthrough emesis:
-Occurs despite adequate antiemetic therapy Phases of Chemotherapy Induced Nausea and Vomiting (CINV) Negative risk factors
Chronic alcohol ingestion
Previous treatment with chemotherapy with good emetic control Positive risk factors
Women
Children
Susceptible to motion or morning sickness
History of depression
Psychosocial issues CINV Risk Factors Emetogenicity of Chemotherapy High (HEC): >90%
Moderate (MEC): 30%-90%
Low: 10%-30%
Minimal: <10% Antiemetics Non-pharmacologic Therapy Eat small, frequent, light meals throughout the dayBRAT diet: bananas, rice, applesauce, toast, or other bland foodsAvoid spicy foods or foods that are irritating to the stomach Slowly advance the diet as symptoms resolveLying down may alleviate some symptoms Drink 8-10 8 ounce glasses of water, sports drinks, or juice per dayMonitor patient for signs and symptoms of dehydration Prevention of CINV—HEC Day 1 --> NK1 --> 5HT3 --> Steroid
Day 2 --> NK1 --> Steroid
Day 3 --> NK1 --> Steroid
Day 4 --> Steroid Prevention of CINV—MEC Without aprepitant Day 1 --> 5HT3 --> Steroid
Day 2 --> Steroid
Day 3 --> Steroid HEC MEC
w/out
aprepitant Prevention of CINV—MEC With aprepitant Reasons to consider NK1 RA in MEC: Less use of dexamethasone, patient with previous poor control, chemotherapeutic agent: carboplatin ≥ 300mg/m2, ≥ AUC 6, cyclophosphamide ≥ 600 mg/m2, doxorubicin, epirubicin Day 1 --> NK1 --> 5HT3 --> Steroid
Day 2 --> NK1
Day 3 --> NK1 MEC
w/ aprepitant None For acute prevention of CINV
Minimal Emetic Risk For acute prevention of CINV
Low Emetic Risk Dexamethasone 8 mg PO/IV x 1 dose For acute prevention of CINV
Low Emetic Risk Dexamethasone 8 mg PO/IV x 1 dose For acute prevention of CINV
Minimal Emetic Risk none Low treatment grading prevention risk factors time frame 0 to 5 days: Asymptomatic redness
0 to 7 days: Desquamation with white patches
6 to 12 days: Contiguous pseudomembranes
12 to 16 days: Painful lesions with or without ulceration
21 to 28 days: Resolution Time Frame Stomatitis/Mucositis Chemotherapy
5-FU
Doxorubicin
Methotrexate
High-dose chemo
Poor dentition, poor fitting dentures
Radiation to the head and/or neck Risk Factors Stomatitis/Mucositis High risk patients
Evaluation by a dentist
Rinse mouth BID-QID during and between courses
Do NOT give chlorhexidine to radiation patients
5-FU, HD melphalan
Oral cryotherapy
HD chemoradiotherapy prior to HSCT
Palifermin Good oral hygiene
Soft toothbrush
Thorough brushing twice daily
Daily flossing
Bland rinses (BID-QID)
Oral moisturizers
Diet
Avoid rough foods, spices, salt and acidic foods
Do not smoke or drink alcohol Stomatitis/Mucositis Prevention Stomatitis/Mucositis common toxicity criteria Stomatitis/Mucositis Treatment Mainly supportive care
Pain management
Topical analgesics
Combination of viscous lidocaine, diphenhydramine liquid, antacid (1:1:1)
Grade 2
Systemic analgesics
Oral or IV (including PCA) opioids
Grades 3, 4
Diet modification
Options
Soft solids
Full liquids
Enteral or parenteral nutrition Continue oral hygiene
Dehydration → intravenous hydration
Local infections
Candida species, herpes simplex viruses (HSV) most common
Culture suspicious lesions
Topical antifungal therapy for mild infections
Severe oral or esophageal fungal infections
Oral fluconazole or intravenous antifungals
Acyclovir for HSV
Do NOT give chlorhexidine rinses Stomatitis/Mucositis Treatment time frame risk factors cross links DNA 0-4 describe each grade cell cycle speficic non-phase specific nitrogen
mustards
(5) methylhydrazine
derivative
(1) alkylating agents mechlorethamine
cyclophosphamide
ifosfamide
melphalan
chlorambucil procarbazine alkyl
solfonate
(1) busulfan nitrosources
(not commonly used
but crosses BBB)
(4) streptozocin
lomustine
carmustine
bendamustine triazines
(2) dacarbazine
temozolomide platinums
(3) cisplatin
carboplatin
oxaliplatin antitumor antibiotics anthracycline
antibiotics
(4) anthracenedione
(3) daunorubicin
doxorubicin
epirubicin mitoxantrone
bleomycin
mitocmycin C antimetabolites purine analogs
(4) pyrimidine analogs
(5) folic acid analogs
(2)
pentostatin
fludarabine
clofarabine
nercaptopurine 5-flurouracil, capecitabine
cytarabine
gemcitabine
decitabine
5-azacytidine methotrexate
pemetrexed vina
alkaloids
(3) taxanes
(3) epolithilones
(1) miscellaneous
(1) vinblastine
vinorelbine
vincristine Ixabepilone (used in met. breast CA) eribulin paclitaxel
docetaxel
cabazitaxel antimicrotubules topoisomerase inhibitors epipodophyllotoxins
(2) camptothecins
(2) etoposides
teniposide topotecan
irinotecan MOA cross link DNA intercalates
DNA no unwinding microtubules nucleic acids antimetabolite antimicro tubules topoisomerase
inhibitors alkylating
agents antitumor
antibiotics 3 drugs &
3 other things for diet modification
grade 2
grade 3,4 wharn does leukopeni begin?
when is the nadir?
when does reovery start?
when 3 drugs/class have delayed neutropenia?
how long does it last? pp Toxicity may include interstitial pulmonary fibrosis, hyperpigmentation, seizures, hepatic (veno-occlusive disease) and wasting syndrome. Busulfan also induces thrombocytopenia, a condition of lowered blood platelet count and activity MASS common toxicities N/V
myelosuppression
vesicants
Mucositis
Alopecia
Sterility/infertility
Seconday malignancies N/V
myelosuppression
vesicant
Mucositits/stomatitis
Alopexia hematologic
neutropenic
thrombocytopenic myeosuppression
peripheral neuropathy
HSN
constiptation
neurotoxicity
vesicant
fluid retention
N/V
myelosuppression
Mucositis
skin and nail changes antimetabolite antimicro tubules topoisomerase
inhibitors alkylating
agents antitumor
antibiotics (except bleomycin) (except bleomycin) (except bleomycin &
. mitoxanterone) etoposide:
HoTN
myelosuppression
Mucositis/STOMATITIS
Alopecia
Diarrhea
topotecan:
N/V
myelopsuppression
Mucostitis
Alopecia
irinotecan:
myelosuppression
diarrhea
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