PHARM 2 lectures (treatment of cancer complications, targeted therapy) Flashcards
aspirin, acetominophen, ibuprofen, ketorolac are
NSAIDS
morphine, hydromorphine, fentanyl, oxycodone, codeine are all
opioids
Adjuncts for neuropathic pain
antidepressants (tricyclic) anticonvulsants local anesthetics bisphosphonates (for bone pain) psycostimulants (eg methylphenidate for fatigue)
drugs for treating nausea and vomiting
5-HT3 antagonists (eg ondansetron)
steroids (eg dexamethasone)
antidopaminergics (eg metoclopramide, haloperidol)
neurokinin 1 antagonists (eg aprepitant
nausea/vomiting adjuncts
benzos (eg lorazepan for anticipatory nausea)
H2 antagonists and proton pump inhibs (diphenhydramine and omeprazole)
cannabinoids (eg dronabinol)
antipsychotics/phenothiazines (eg promethazine)
Examples of colony stimulating factors (CSFs)
Filgrastim (GCSF), pegfilgrastim, sargramostim
What types of N/V can cisplatin cause
chemo-induced (min to hours), delayed (after a day), anticipatory (v highly emetic agent)
Most emetogenic compound known?
CISPLATIN!
Drug combos for highly emetic tx
- 5HT3 antagonists (ONDANSETRON)
- steroids (DEXAMETHASONE)
- Neurokinin-1 antagonists (AREPITANT) and adjuncts (benzos, PPIs such as OMEPRAZOLE)
Drug combos for low emetic tx
steroids, benzos, PPIs
-ANtidopaminergics (metoclopramide, prochloroperazine for motion sickness aka composine, haloperidol)
What are metoclopramide and haloperidol used for/ what type of drug?
antidopaminergic, for low emetic tx
Drugs for breakthru emesis
ADD, dont remove
-antipsychotics (olanzapine), cannabinoids (such as DRANABINOL aka marinol), phenothiazines (PROCHLORPERAZINE, PROMETHAZINE), 5ht3 antagonists, steroids
Tx for anticipatory nausea
BENZOS (lorazepam, also anti-anxiety)
acupuncture/pressure, behavioral
3 types of pain to be treated
SOMATIC (most common, well localized, paine from bone metas, PGs sensitive nociceptors)
VISCERAL (deep, squeezing, colicky aka waves, often from obstufction, hard to localize)
NEUROPATHIC (second most common, tumor eroding into nerve, or chemo causing neuro dmg, burning/electrical paroxysmal aka sudden/short/freq)
How do NSAIDS treat pain
inhib PGs which sensitize nociceptors, no tolerance/dependency issues, some GI/liver/nephrotoxicity
NSAIDs examples
ASA/acetominophen
Ibuprofen, naproxen
Salsalate (doesnt affect platelets)
Ketorolac (can be given IV)
Weak opiate examples (2)
Codeine (must be conv to morphine in liver by p450, some ppl cant make conversion)
Oxycodone
Strong opiates
Morphine
Hydromorphone
Methadone
Fentanyl (avail as topical patch)
Why shouldnt meperidine be used?
causes seizures
Drug examples for neuropathic pain
not opiates
tricyclics, antidepressants, anticonvulsants, local anesthetics (eg gapapentin, lyrica) (for neuropathic pain NOT general pain!)
What is bone pain treated with
bisphosphonates (pamidornate, zoledronic acid)
INHIBITS OSTEOCLASTS
Morphine side effects
CONSTIPATION (tx with lactulose or senna, NOT stool softeners), morphine causes gut not to move, so use a stimulate laxative
- itching: tx with H1 antagonist
- somnolence (sleepy) use psychostimulants
- nausea (usu gets better)
- resp depression
How to treat fatigue induced by cancer tx
Methylphenidate (or caffiene/beh tx)
Erythropoeisis stimulating agents have no effect “poeitin”
How to treat marrow suppression
can get neutropenia etc so more sus to bacterial infxn, put on antibiotics, and CSFs for anticipation of febrile neutropenia (filgrastim,peg, sagro, etc)
marrow suppressive agents
“taxels”, cisplatin, etc
Myeloid stimulating agents
When should CSFs be given?
Filgrastrin (GCSF), stim marrow to produce more neutros
- pegfilgrastim
- sargramostim (GMCSF)
- Should be given BEFORE chemo to prevent neutropenia, not with (toxic) or after
What can giving CSFs WITH chemo cause?
major toxicity (all the -stims, ARDS, pain, rash, feber, etc)
Dont use EPO drugs for anemia–why?
dont work and can cause tumor progression
What are CSFs used for
to mediate anticipated neutropenia!
Most common estro receptor targets
tamoxifen, anastrazole
Andro receptor targets
GNRH analogs
Bcr/abl targets
Imatinib
EGFR
erlotinib
VEGF target
bevacizumab
Immunologic therapies:
PD-1.PDL-1 monoclonals
nivolumab
CTLA-4 tx
ipilimumab
TAMOXIFEN TOX
incr risk of endomet cancer, thrombus, depr/menopause sx
ANASTRAZOLE (AI) toxicity???
very safe
andro depriv tx (GNRH agonists) tox???
no sxe
IMATINIB (TKI against bcr-abl) TOX?
well tolerated but some hepatotoxicity
ERLOTINIB (TKI against EGFR) TOX?
same as prev
NIVOLUMAB (anti PD-1 checkpoint blockade) TOX?
ab tx: some fatigue, flu sx, allergic rxn
rare: low blood cell, skin rxns, bleeding
IPILIMUMAB (anti CTLA-4 checkpoint) TOX?
SAME AS PREV
SIPULCEL-T (dendritic cell vaccine) TOX?
no sxe
CAR-T CELLS TOX?
cytokine storm,
toxicities related to spec ag used
What can prophylatic tamoxifen prevent
BC in high risk women
What is Tamox assoc with
DVTs and UTERINE CANCeR
what is better to use in post menopausal women than tamox
aromatase inhibts
what tx should all BC women with ER/PR + BC receive
antiestrogen tx
What are 4 types of MOLECULAR INHIBITORS avail to tx cancer
Endocrine tx
TKIs
CDK inhibs
PARP inhibs
What are 4 types of immunotherapies against cancer?
Monoclonal abs
Dendritic Cell therapy
Immune checkpoint blockade
Adoptive T cell Tx
Why is targeted tx better than chemo
doesnt kill all cells, only some are cytotoxic, specific, many agents are oral instead of IV
what do targeted cancer tx generally do?
turn off division signals, change prots in cell so they undergo apop, stop neoangiogenesis, trigger immuns sys to destroy cells, deliver toxin to cancer cell only
What does ER do in cancer
estro signaling causes cancer to prolif
estro receptor binds to estro in cyto, dimeraizes with another, head to nucl to activate TF for gene transcr
What do SERMs do? main example
eg TAMOXIFEN!
Selective ER modulator: binds to ER, reducing transcr, bloks G1phase progression, cytostatic (wont kill cells)
When are SERMs used?
Gold standard for adjuvant tx (tx after tumor removal) in ER + BCs, esp POST-menopausal (DONT use if cancer is ER -) bc will be ineffective
Ancillary benefits and toxicities of SERMs (tamox)?
How can tamox resistance occur?
ancillary benefits: less CV issues, less bone fractures
- toxicity: INCR RISK OF ENDOMETR CANCER, THROMBOEMBOLISM, depr/menopause sx
- resistance: many paths, eg aromatase (producing estrogen anyway thru alternative signalign), eg ER mutation or Her-2 signaling
Aromatase inhibitors (AIs)
aromatase conv andro to estro in periph (usu in post-meno)
- use as 2nd line tx when tamox not suff, instead of steroid
- v safe
Aromatase inhibs generations and main gen III drug?
The 2 types of aromatase inhbits?
1st-3rd gen, main gen III is ANASTRAZOLE (also extremestane and letrozole)
-2 types: I enzyme inactivators (steroidal), and II competitive antagonists (no steroidal)
Impt anti-estrogen drug
FULVESTRANT
LHRH (GnRH) agonists
decr prod of estro thru neg feedback on HPA
Ideal treatmetns for ER+ cancers?
Tamox and AIs
Androgen deprivation tx
VERY successful in men with advanced prostate cancer
(ADT)
ablate androgen sources and synth etc
What drugs are involved in ADT
GNRH agonists mostly, GnRH antagonists, adrenal ablating durgs, andro rec antagonists, 4-a-reudctase inhibts
How do GnrH agnosits work
lots of gnrh, body responds by down reg pit gnrh receptors, so less LH rel, so less test prod
What are the 3 ways BC and PC can be resistant to endocrine tx?
1 subversion: mutation in receptor causes abnormal phosphorylation patterns
2 opportunity: cell signal interrupted so creates more receptors (eg if her2/neu blocked with drugs, might overexpress receptor)
3 redundancy: mutation/deletion in rec can make it const active so doesnt need bound ligand to cause growht
suffix for TKIs?
“NIB”
what do TKIs do?
Tox?
target tyroskine kinases to target prolif
well tolerated but some hepatotox
-not used by selves
-antiVEGF can cause HTN bc limits blood vessel growth
Which drug targets BCR-ABL
IMATINIB (aka gleevec) binds to fused gene and decr activitity (use for CML/ALL)
What tx do we use for EGFR targeting?
ERlotinib (and gefitinib)
prevents overactive epidermal growht factor receptor activity
CDK inibts
CDK4 and CDK6 are most common targets
inhib overactive CDKs so inhib overactive cell cycle
PARP inhibs
Poly ADP-Ribose polymerase inhibs (DNA repair enzyme by cancer cells to go thru cell cycle fast) (BRCA 1/2 fxn similarly)
- best suited for BRCA - tumors (if no BRCA oncogene, PARP is responsible for DNA repair)
- prevents repair and leads to tumor cell death
- long half life, bbb penetration, some liver issues like others
Antibody therapy
monoclonal antibodies against cancer ags, bind and kill cells thru complement act, ADCC, neutralize, oposonize, etc etc
-conjugated is attached to radioactive cpd or toxin
2 drugs that are ab therapies for cancer
NIVOLUMAB (PD-1/PDL1 mab)
BEVACIZUMAB (anti-VEGF mab, prevents blood supply to tumors)
side effects of ab tx?
fatigue, flu like sx, allergic rx to ab (rarely low blood count, skin issues, infusion rxn)
First tumor vaccine
SIPULEUCEL-T
- remove dendritic cells, then activated by tumor ags and then returned to body (vaccine made of pts own DCs!)
- active
Immune checkpoint blockade
interaxn bn APC and T cell
What does NIVOLUMAB do?
anti-PD-1 mab
-used for PD-L1 + tumors, binds PD-1 so that PD-1 doesnt deactivate T cells
What does IPILIMUMAB do?
Anti-CTLA-4 (CTLA-4 usu inhibs T cells and binds ot B7 on APCs), ipilimumab binds CTLA-4 but doesnt signal, so it wont bind B7 (instead, b7 can now bind more to CD28 and excite T cells)
What does tx with CAR T-CELLS DO?
cell based gene tx
T cells removed and tarnsudced with CAR (chimeric antigen receptor)
-adv: live drug, engineers NK and CD8 cells to kill tumor
Toxicity of CAR T-cells? Tx for toxicity?
- toxicity: cytokine storm: elevates pro inflamm cytos causing shock and death
- tx this to with anti-IL6 and steroids
What procedures can we do if we know someone has BRCA
reduce risk of cancer thru prophylactic oophorectomy and mastectomy
(with high risk cancer, can even use tamox prophylactically)
