IC5 Flashcards
Describe the peripheral pathway of CINV
- Peripheral pathway responsible for acute CINV
- The GIT since it has fast reproducing cells
- Chemotherapy kills these fast reproducing cells
- Serotonin release causing CINV
Describe the central pathway of CINV
- Central pathway responsible for delayed CINV
- CNS along with chemoreceptor trigger zone
- NK1 release causing CINV
Acute CINV
- Starts 1-2h after administration
- Peaks at 5-6h
- Resolves at 12-24h
Delayed CINV
- Peaks at 48-72h
- Resolves in 1-3 days
Breakthrough CINV
CINV occurs despite preventive therapy
Anticipatory CINV
Uncontrolled emesia prior to chemotherapy
Refractory CINV
Antiemetic prophylaxis or rescue therapy has failed in previous cycles
Risk factors for CINV
- Age < 50 years
- Female
- History of low prior alcohol intake, patient is not a chronic drinker: < 1 glass per day
- History of previous chemotherapy induced emesis, vomited with chemo drugs
- History of motion sickness
- History of emesis past pregnancy
- Anxiety
High emetogenic risk drug combination
NK1 (day 1) + 5HT3 (day 1) + Dexa (day 1-4) +/- Olanzapine (day 1-4)
Moderate emetogenic risk drug combination
5HT3 (day 1) + Dexa (day 1-3)
Low emetogenic risk drug combination
5HT3 or Dexa or Dopamine antagonist (all day 1 only)
NK1 antagonist indication
Acute and delayed CINV
Examples of NK1
Aprepitant PO 125mg OD day 1, 80mg OD day 2 and 3 (3 day course)
Akynzeo: PO Netupitant 300mg + Palonosetron 0.5mg OD day 1 (NK1+5HT3)
ADR of NK1 antagonist
Fatigue, weakness, nausea, hiccups
DDI of NK1 antagonists
NK1 antagonists are CYP3A4 inhibitors
- Steroids, warfarin, benzodiazepines, ifosfamide
5HT3 antagonist indication
Acute CINV only
Examples of 5HT3 antagonist
Ondansetron PO/IV 8-16mg OD day 1, 8mg OD day 2 onwards
Granisetron PO/IV 1mg OD day 1, 1mg OM day 2 onwards
ADR of 5HT3 antagonist
QTC prolongation (black box)
Headache, constipation
Dexamethasone indication
Acute and delayed CINV
Examples of dexamethasone
Dexamethasone PO/IV 12mg OD day 1, 8mg OD day 2 onwards
ADR of dexamethasone
Elevation of blood glucose
Insomnia, anxiety, GI upset
Psychosis, reactivation of ulcers
Olanzapine indication
Acute and delayed CINV
Examples of olanzapine
Olanzapine PO 5-10mg OD
Elderly: 2.5mg OD
ADR of olanzapine
Fatigue, sedation, postural hypotension, anticholinergic side effects (dry mouth, blurred vision, urinary retention)
Metoclopramide indication
Acute and breakthrough CINV
Example of metoclopramide
Metoclopramide PO/IV 10mg OD-TDS prn
ADR of metoclopramide
Sedation, diarrhoea, EPSE – akathisia, dystonia
DDI of metoclopramide
Metoclopramide + Olanzapine = increased risk of EPSE – tardive dyskinesias, neuroleptic malignant syndrome
Benzodiazepines indications
Anticipatory CINV
Example of benzodiazepines
PO Alprazolam 0.5mg-1mg night before treatment + 1-2h before chemotherapy
PO Lorazepam 0.5mg-2mg night before treatment + 1-2h before chemotherapy
ADR of benzodiazepines
Drowsiness, dizziness, hypotension, anterograde amnesia – cannot form new memories, paradoxical reactions – hyperactiveness, aggression
Non-pharmacological management of anticipatory CINV
- Relaxation, music therapy
- Hypnosis, guided imagery
- Systematic desensitisation
Adjunctive agents indication
Refractory CINV
Examples of adjunctive agents
Haloperidol (Butyrophenones)
Dose: PO/IV 0.5-2mg q4-6h
ADR: EPSE, sedation
Prochlorperazine, chlorpromazine, promethazine (Phenothiazines)
Dose: PO Prochlorperazine 10mg TDS/QDS prn
ADR: drowsiness, hypotension, EPSE
Non-pharmacological management of CINV
- Take small, frequent meals, avoid heavy meals
- Avoid greasy, spicy, very sweet or salty food or foods with strong flavours or smells
- Sip small amounts of fluid often instead of drinking a full glass at one time
- Avoid caffeine containing drinks or foods
- Avoid lying flat for 2h after eating
- Suck on lemon drops
Management of breakthrough CINV
- Add on agent from different drug class different MOA
- If PO route not feasible due to vomiting, use IV route
- Hydration and fluid repletion for losses
- Reassess next cycle’s antiemetics for appropriateness
Risk factors for CID
- Age > 65 years
- Female
- Eastern Cooperative Oncology Group (ECOG) performance status of at least 2
- Bowel inflammation or malabsorption
- Bowel malignancy
- Biliary obstruction
- First cycle of chemotherapy
- Cycle duration of greater than 3 weeks
- Neutropenia, anaemia
- Mucositis
- Vomiting, anorexia
Grade 1 CID
Increase in loose stools < 4 times a day above baseline
Grade 2 CID
Increase in loose stools 4-6 times a day above baseline
Limiting activities of daily living
Grade 3 CID
Increase in 7 or more stools per day above baseline
Limiting self care
Hospitalisation needed
Grade 4 CID
Life threatening, urgent intervention needed
Grade 5
Death
Uncomplicated CID
Grade 1 or 2
No complicating signs and symptoms
Complicated CID
Grade 3 or 4
OR
Grade 1 or 2 with at least 1:
- Cramping
- > grade 2 n/v
- Decreased performance status
- Fever
- Sepsis
- Neutropenia
- Frank bleeding: fresh bleed
- Dehydration
Goals of therapy for CID
- Improve recovery of intestinal mucosa
- Improve QOL and ADL
- Decrease morbidity and mortality from CID
- Decrease hospitalisation
Pharmacological management of uncomplicated CID
Diarrhoea lasting <12h
- PO Loperamide 4mg, then 2mg q4h or after every episode, max 16mg per day
- Continue until 12h free of diarrhoea then stop
- If patient cannot tolerate/swallow loperamide, can use diphenoylate/atropine
Diarrhoea lasting >12-24h
- PO Loperamide 2mg q2h
- PO Antibiotics for infection prevention
- Start octreotide or other second line agent
Pharmacological management of complicated CID
- SQ Octreotide 100-150mcg TDS
- Or IV Octreotide with dose escalation up to 500mcg TDS
- IV fluid hydration
- IV antibiotics: Ciprofloxacin x 7 days
MOA of irinotecan induced diarrhoea
- Irinotecan converted to SN38 (active metabolite) which is very cytotoxic, responsible for diarrhoea
- SN38 deactivated by glucuronidation to SN38-G (inactive metabolite) by UDP-GT 1A1 in liver
- Presence of irinotecan alters commensal bacteria in gut
- Bacteria in gut produce beta glucuronidases
o Reactivate SN38G SN38 via deconjugation
o SN38 damages gut mucosa during excretion - Leads to ablation of crypts, villus blunting, atrophy of epithelium in small and large intestine
Pharmacogenomics of irinotecan induced CID
- SN38 deactivated by glucuronidation to SN38-G by UDP-GT 1A1
- Homozygous for UGT1A1*28 decreased expression of UDP-GT 1A1 increased toxicity, more diarrhoea
Pharmacological management of irinotecan induced diarrhoea
Acute onset < 24h
- SC/IV Atropine 0.25-1mg (Max 1.2mg) – usually SC
- Indication: acute onset irinotecan induced diarrhoea
- MOA: Atropine is a competitive antagonist which inhibits acetylcholine at muscarinic receptors
- ADR:
o Insomnia, dizziness
o Tachycardia, blurred vision, dry mouth
o Constipation
- Contraindicated in glaucoma
Late onset
- PO Loperamide 4mg after first diarrhoea, then 2mg every 2h, no max dose (special dosing)
o Dose 4mg every 4h so patient don’t have to keep waking up
o Stop when 12h passes without any bowel movement
ADR of loperamide
- Constipation, abdominal pain, dizziness, rash, bloating, nausea and vomiting, dry mouth, drowsiness
- High doses associated with paralytic ileus (muscles and nerves of intestine stop working)
ADR of octreotide
- Bradycardia, arrhythmias
- n/v/c
- Headache, dizziness
- Enlarged thyroid
Non-pharmacological management of CID
- Probiotics with Lactobacillus prevent CID
- Diet modification
o Avoid
o Caffeine, alcohol, fruit juice,
o Lactose containing foods at least 1 week after CID resolved loss of lactase activity
o Spicy foods
o High in fat or fiber
o Dietary supplements with high osmolarity - Have small frequent meals
- Bananas, rice, applesauce, toast (BRAT) diet
- Take at least 3L of clear fluids containing salt, sugar and electrolytes
Risk factors for constipation
- Lowered fluid intake, dehydration
- Loss of appetite, anorexia
- Lack of fibre or bulk forming foods in diet
- Iron, calcium supplements
- Low physical activity, bed rest
- Overuse of laxatives
- Thyroid problems, depression
- High Ca or K in blood
- Cancer in large intestine or pressing on spinal cord\
- Medication induced
o Pain relief: morphine, codeine
o Chemotherapy: Vincristine, vinblastine, vinorelbine
o Antiemetics: Ondansetron, granisetron, anticonvulsant drugs
Prevention of constipation
- Eat more fibre: soluble and insoluble fibre
- Eat natural laxatives: prunes, fruits with high fibre
- Increase physical activity gradually since chemo makes patient tired
Pharmacological management of constipation
- Stool softeners
- Laxatives
- Stimulate bowel activity: Senna 15mg ON, lactulose 10mg TDS, mineral oil
- Increase fibre or produce bulk: Psyllium, PEG (forlax, fybogel) 1 sachet BD
- Enemas
- Fleet (phosphate), tap water
- Suppository
- Glycerine, bisacodyl
- Enemas and suppository not recommended when WBC or platelet count low due to risk of infection or bleeding
- Only use enemas or suppositories if constipation is very bad
Grade 1 mucositis
Mild, no intervention
Grade 2 mucositis
Moderate pain, modified diet
Grade 3 mucositis
Severe pain, interferes with PO intake
Patient related risk factors for mucositis
- Autoimmune disorders
- Diabetes
- Female for 5FU
- Caucasians > African American
- Genetic predisposition to tissue damage: deficiency in enzymes responsible fro metabolising chemotherapy
- Folic acid or vitamin B12 deficiency
Treatment related risk factors for mucositis
- Varies by agent and regimen
- S-phase specific agents have highest risk
- Duration, dose intensity, schedule
- Prolonged or repetitive lower doses higher risk > bolus doses.
- Risk increases with number of cycles
- Risk increases when clearance of chemotherapy is delayed by renal or hepatic impairment
- Previous therapies toxic to mucosa
- Risk increases with previous episodes of mucositis
- Radiation added on to chemotherapy
- Dependent on radiation source, dosage, dose intensity and volume of mucosa irradiated
- Smoking
- Alcohol consumption
- Xerostomia and infection
Prevention of mucositis
- Oral cryotherapy: suck on ice chips
- Vasoconstriction so chemo drug doesn’t go to mucosa and cause mucositis
- IV Palifermin 60mcg/kg/day x 3 days
- Reduces severity and duration of oral mucositis
- Extremely costly
- Benzydamine HCL
- Good oral hygiene: use a soft toothbrush, gargle with salt water after each use
- Laser therapy after radiation: not done in SG
Pharmacological management of mucositis
- Oracare suspension
- Mylocaine suspension
- Morphine sulfate solution
- Oracort E paste
- Soragel
- Medijel
- Difflam gargle/soray: benzydamine
Non-pharmacological management of mucositis
Alcohol free mouthwashes
- Oral7 mouthwash
- BioXtra mouthwash
Do not use alcohol containing mouthwash due to the drying effect
