Lec 6 Heme/Onc
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What mechanisms are involved in chemotherapy-induced n/v?
- chemoreceptor trigger zone: chemical stimuli in CSF and blood (chemo)
- neurotransmitter receptors in GIT & vagus nerve stimulation: chemo & GI compression
What are the patient-related risk factors for CINV?
- poor control with previous chemo
- psychosocial (anxiety, depression, etc)
- age <50
- alcohol use history (<10 drinks/wk)
- hx of motion sickness or morning sickness w/ pregnancy
What are the therapy-related risk factors for CINV?
- emetogenic potential of chemo regimen
- dose, route, and administration rate of agent
- multiple chemotherapy cycles
- concomitant radiation
What is acute CINV and what is its MOA?
- occurs within 1st 24 hours of chemo
- peaks in 5-6 hrs
- mechanism: stimulation of dopamine & serotonin receptors
What is delayed CINV and what is its MOA?
- occurs > 18-24 hrs after chemo and up to 5 days later
- peaks at 2-3 days post-chemo
- mechanism: stimulation of dopamine and serotonin receptors
What is anticipatory CINV and what is its MOA?
- triggered by sights, smells, sounds
- often due to poor past control
- can occur at any time
- mechanism: conditioned reflex - not d/t nueroreceptor stimulation
What is breakthrough CINV and what is its MOA?
- occurs despite prophylactic treatment
- requires the use of rescue therapy
Which drugs have high (>90% of patients) emetogenic risk?
Which drugs have moderate (> 30% of patients) emetogenic risk?
What classes of drugs are used in the prevention and management of CINV?
- neurokinin-1 antagonists
- serotonin antagonists
- benzamide analogs
- belladonna alkaloids
Discuss neurokinin-1 antagonists.
- Emend (aprepitant, fosaprepitant)
- aprepitant: acute/delayed
- fosaprepitant: acute
- approved in combination with other antiemetics for prevention of acute and delayed n/v
- appropriate for pt receiving moderate emetogenic chemo (anthracycline & cyclophosphamide) & possibly other types of chemo associated w/ delayed CINV
- substrate of CYP 3A4
- 3 days administration: CYP3A4 inhibitor
- > 14 days administration: CYP3A4/CYP2C9 inducer
- warning: several case reports of ifosfamide-induced encephalopathy in pt receiving aprepitant
Discuss serotonin antagonists
- Kytril (granisetron), Zofran (ondansetron), Aloxi (palonosetron) --> acute treatment
- recognized as the foundation of CINV management
- most commonly used meds to prevent and treat acute n/v
- MOA: blocks release of serotonin from enterochromaffin cells in the GIT & blocks release of serotonin from receptors in the medulla
- AE: h/a, constipation, asthenia, diarrhea, sedation; asymptomatic & transient ECG inteval abnormalities (PR, QT, ST prolongation & QRS widening)
- studies show these drugs not very effective if used after day 1 of chemo
Whcih serotonin antagonist should be administered with a corticosteroid and be given as a 1 time dose on day 1 only?
- decadron (dexamethasone): acute and delayed
- MOA: questionable inhibition of prostaglandin synthesis in cortex, decreased serotonin turnover in CNS, modulation of higher coritcal pathway; synergistic with seronitin antagonists and metoclopramide
- AE: mood changes, anxiety, insomnia, increased appetite, hyperglycemia, mild fluid retention, perinieal, vaginal, and anal burning (rare- caused by too rapid of IV administration)
Discuss benzamide analogs.
- Reglan (metoclopramide) and Tigan (trimethobenzamide)
- MOA: blocks dopamine effect at chemoreceptor trigger zone, stimulates cholinergic activity in the gut therefore increasing gut motility, blocks peripheral serotonin receptors in the gut
- highly emetogenic agents: requires high doses & combo w/ diphenhydramine/lorazepam
- moderately/milk emetogenic agents: lower doses
- AE: EPS (dystonia, trismus), akathisia
- Compazine (prochlorperazine) and Phenergan (promethazine)
- MOA: blocks dopamine and histamine receptors
- AE: sedation, hypotension, akathisia, dystonia
- prochlorperazine has greater efficacy for delayed nausea than serotonin antagonists
- effective with mild/moderately emetogenic chemo (mostly prn)
- not very potent antiemetic in cancer pts - breakthrough meds
- MOA: blocks dopamin receptors in the CTZ
- at least equally efficacious as phenothiazines (binds differently due to chemical structure; alternative if phenothiazines fail)
- useful for breakthrough n/v
- AE: sedation, anticholinergic effects, hypotension (less common than w/ phenothiazines), EPS uncommon, QT prolongation (possibly w/ droperidol)
- Lorazepam by itself has minmal to no activity as an antiemetic
- useful to prevent anticipatory n/v
- AE: amnesia, sedation, hypotension, hallucinations, urinary incontinence, disinhibition, motor incoordination
- Dronabinol, Nabilone
- MOA: targets CB1 receptor in the CNS to directly block emesis; indirectly inhibits other NTs release in the emesis process
- Interactions: metabolized by 2C9; may inhibit 3A4
- AE: drowsiness, euphoria, dysphoria, mood changes, orthostatic hypotension, ataxia, hallucinations, time disorientation , increased appetite
- Dronabinol: included in the most recent antiemetic guidelines; effective with mild to moderate emetogenic chemo
- tolerance usually develops to AEs
Discuss belladonna alkaloids.
- scopolamine patch
- MOA: blocks ACh receptors in vestibular apparatus
- AE: dry mouth, sedation, impaired eye accommodation
- useful in pt whose n/v is positional or due to motion
What are non-pharm therapy for CINV?
- acupuncture (shows mild improvement in vomiting, not nausea)
- guided imagery
- music therapy
- progressive muscle relaxation
- psychoeducational support
- acustimulation with wristband device
- dietary changes: smaller, more frequent meals; foods w/ reduced aroma; avoid spicy, fatty or salty foods; take anti-emetics prior to meals; eat gentle, comfort foods
What is the acute n/v treatment for Hesketh level of 4 or 5?
serotonin antagonist (zofran) AND dexamethasone AND (fos)aprepitant
What is the acute n/v treatment for Hesketh level of 3?
serotonin antagonist AND dexamethasone +/- (fos)aprepitant
What is the acute n/v treatment for Hesketh level of 2?
prochlorperazine OR dexamethasone OR metoclopramide
What is the acute n/v treatment for Hesketh level of 1?
no routine prophylaxis
What is the delayed n/v treatment for Hesketh level of 3, 4 or 5?
dexamethasone +/- aprepitant
What is the delayed n/v treatment for Hesketh level of 1 or 2?
no routine prophylaxis
What is the procedure for breakthrough emesis?
- give drug from different class
- around the clock - avoid prn
- IV > PO
- reassess prior to next cycle
What should be reassessed prior to the next cycle of chemo for breakthrough emesis?
- add aprepitant?
- increase dose/frequency of serotonin antagonist? change serotonin antagonist?
- add anxiolytic?
- change chemo? (palliation)
- consider addition of H2 blocker or PPI (dyspepsia)
When are anti-emetics best?
- when given prophylactically
- 5-30 minutes prior to chemo
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