Supportive and Palliative Care Flashcards
List the drug class useful for anticipatory nausea/ vomiting
Benzodiazepine
List the classes that are useful for BOTH acute and delayed nausea/ vomiting (3+1)
NK-1 antagonist
Corticosteroid
Olanzapine
Dopamine Antagonist (less useful)
State which drug class only useful for acute n/v but not delayed
5HT3 Antagonist
State the definition of:
a) Acute
b) Delayed
c) Breakthrough
d) Anticipatory
e) Refractory N/V
Acute:
- Usually starts within 1-2 hours after administration
- Peak intensity within 5-6 hours, resolution at 12-24 hours
Delayed:
- Peak onset 48-72 hours after chemotherapy, diminishing after 1- 3 days
- Occurs in 50-90% (highly emetogenic regimens), 35%-80% (moderately emetogenic therapy) of patients
Breakthrough:
- N/V occurring despite preventive therapy
Anticipatory:
- Conditioned response (e.g due to fear of chemo)
- Associated with uncontrolled emesis prior chemotherapy
Refractory:
- N/V occurring during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in previous cycles
- May involve use of multiple antiemetics, even those with lesser evidence
List the risk factors for CINV (7) (Hint: think of what cause puking)
1) Younger age (<50 years old)
2) Female gender
3) History of low prior chronic alcohol intake (<1 glass of alcohol/day)
* Alcohol use is protective factor
4) History of previous chemotherapy induced emesis
5) History of motion sickness
6) History of emesis during past pregnancy
7) Anxiety
List the ADRs of NK-1 antagonist (4)
fatigue, weakness, nausea, hiccups, headache, constipation
List the ADRs of 5HT3 antagonist (3)
Headache and constipation, QTc prolongation, Hiccup
List the classes reserved for refractory n/v
- Butyrophenones (haloperidol)
- Phenothiazines (prochlorperazine, chlorpromazine, promethazine)
List non-pharmacological management of CINV (6)
o Take small, frequent meals. Avoid heavy meals.
o Avoid greasy, spicy, very sweet or salty food and food with strong flavors or smells.
o Sip small amounts of fluid often instead of trying to drink a full glass at one time.
o Avoid caffeinated beverages.
o Avoid lying flat for 2 hours after eating.
o Suck candies such as lemon drops
List the general steps in managing breakthrough N/V (4) (Hint think of reasons why this may occur and consequence of this occuring)
o General principle is to give an additional agent from a different drug class -> see what N/V pathway hasn’t been blocked
o Choice of agent should be based on assessment of the current prevention strategies used
o Consider use of several agents utilizing different mechanism of actions if necessary
o If PO route not feasible due to ongoing vomiting, consider IV route
o Hydration and fluid repletion for losses (consider oral rehydration salts)
o Reassess next cycle’s antiemetics to ensure anti-emetic regimen is appropriate
List the steps in the management of Anticipatory CINV (4)
1) Prevention is key -> Use optimal anti-emetic therapy during every cycle of treatment
2) Behavioral therapy
* Relaxation/systematic desensitization
* Hypnosis/guided imagery
* Music therapy
3) Acupuncture/ acupressure
4) Consider use of benzodiazepines before treatment
Risk Factors for CID (~10)
o 1) Age greater than 65 years
o 2) Female
o 3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of at least 2
- How fit the patient is; 0 means very fit, more than 2 is not so fit. Fit = ability to do daily activities
o 4) Bowel inflammation or malabsorption
o 5) Bowel malignancy
o 6) Biliary obstruction
o Other predictive factors may include first cycle of chemotherapy, cycle duration greater than 3 weeks, concomitant neutropenia, other symptoms such as mucositis, vomiting, anorexia, or anaemia.
State the criteria for Uncomplicated CID
- Grade 1 (Increase of < 4 stools per day above baseline) or 2 (Increase of 4-6 stools per day above baseline + Limiting activities of daily living)
- No complicating signs or symptoms
State the criteria for complicated CID
- Grade 3 or 4
- Grade 1 or 2 with at least one of the following:
o Cramping
o >Grade 2 nausea or vomiting
o Decreased performance status
o Fever
o Sepsis
o Neutropenia
o Frank bleeding
o Dehydration
Goals of therapy for CID? (5)
o CTCAE Grade 0 or 1
o Decrease morbidity and mortality from CID
o Improve quality of life and activities of daily living.
o Improve recovery of intestinal mucosa.
o Decrease hospitalization
What are the non-pharmacological ways to manage CID? (7) (Hint: think of what chemo does to the gut, what causes diarrhea)
o Probiotics with Lactobacillus are suggested to prevent chemotherapy- or radiation induced diarrhea.
o Avoid caffeine, alcohol, fruit juice, foods that contain lactose, foods that are spicy or high in fat or fiber, or dietary supplements with high osmolarity.
* Up to 10% of patients experience 5-FU–induced lactose intolerance because lactase activity can be lost temporarily.
o Lactose-containing foods should be avoided for at least a week after CID has resolved.
o Eat small, frequent meals.
o BRAT diet (bananas, rice, applesauce, toast)
o More than 3 L of clear fluids containing salt and sugar
o Electrolyte-containing fluids are ideal.
State the general management of uncomplicated CID (including what to do if diarrhea persists for longer than 24hr and after 48 hour)
1) Withhold chemotherapy for grade 2. -> only applicable for PO not so much for IV
* a) Resume when symptoms resolve
* b) Consider dosage reduction of drug
* Note: requires consideration of risk vs benefit as well -> stopping may have the risk of cancer progression as well
2) Diet modifications
* Oral hydration with 8–10 large glasses of clear liquids
* Loperamide 4 mg by mouth, then 2 mg by mouth every 4 hours or after every episode of diarrhea. Continue until 12 hours free of diarrhea, then stop.
* If diarrhea is improving after 12–24 hours, continue with diet modifications and begin to add solid food.
* If diarrhea persists after 12–24 hours:
o a) Schedule loperamide 2 mg every 2 hours.
o b) Start oral antibiotics.
o c) For diarrhea that progresses to severe or complicated, treat as such.
o d) For diarrhea that persists as uncomplicated 12-24 hours after scheduled loperamide (36-48 hours after diarrhea onset), begin octreotide or other second-line agent.
State the management of complicated CID (5) include doses of drugs used
1) Withhold chemotherapy. Resume when all symptoms resolve.
2) Restart at decreased dosage.
3) Administer octreotide 100–150 mcg subcutaneously three times a day or IV with dose escalation up to 500 mcg three times a day.
4) Start IV fluid hydration.
5) Start IV antibiotics (e.g., ciprofloxacin × 7 days). -> concerns about infection
* Note that antibiotics may cause diarrhea too
MOA of Octreotide
Causes decreased hormone secretion, which increases transit time within intestine, decreases secretion of fluid, and increases absorption of fluid and electrolytes
ADRs of Octreotide (8) (think of its MOA)
Bradycardia, arrhythmias, constipation, abdominal pain, enlarged thyroid (hypothyroidism), nausea and vomiting, headache, dizziness
State what liver enzyme deactivates SN-38 and which phenotype increases risk of toxicity
UGT1A1
Those homozygous for UGT1A1 *28
Describe the pathophysiology of irinotecan induced diarrhea
Early onset: Inhibits acetylcholine esterase leading to cholinergic response
Late onset: Mediated by increased formation of SN-38 an active, toxic metabolite -> deactivated by UGT1A1 to SN-38G by liver but once it enters gut, it can undergo deconjugation by beta-glucoronidase by gut bacteria. SN-38 damages gut mucosa during excretion.
Leads to ablation of crypts, villus blunting, and atrophy of the epithelium in the small and large intestine
List the drug and dose used to manage early onset Irinotecan diarrhea
Atropine 0.25–1 mg (maximum 1.2 mg) subcutaneous or IV (usually SC)
just remember 1mg for ease
List the drug and dose used to manage late onset Irinotecan diarrhea
Loperamide 4 mg after first loose bowel movement, then 2 mg every 2 hours (4 mg every 4 hours at night) until 12 hours have passed without bowel movement
ADRs of Atropine? (list most common one, followed by the others)
CI of atropine
Constipation
Insomnia, dizziness, tachycardia, blurred vision, dry mouth
CI: Glaucoma
List the risk factors for constipation (11)
o Lowered fluid intake and dehydration
o Loss of appetite (anorexia)
o Lack of fibre or bulk-forming foods in the diet
o Vitamin or mineral supplements such as iron or calcium pills
o Overuse of laxatives
o Low level of physical activity or a lot of bed rest
o Thyroid problems (Hypothyroidism)
o Depression
o High levels of calcium or potassium in the blood
o Cancer growing into the large intestine (bowel) or pressing on the spinal cord
o Certain drugs (Opioid, Vinca alkaloid, Antinausea, Antidiarrhea, Anticonvulsant)
List the preventive measures for constipation (list any considerations for each measure if any) (4)
o Eat more fibre
-> Not for all patients e.g if patient has CRC, there are rules where can’t eat too much fibre especially if got surgery then don’t want their colon to work as much
o Eat natural laxatives
-> E.g vegetables, coffees, prunes
* But prunes sold in NTUC very sweet -> DM?
o Increase physical activity
o Ensure adequate food and water intake
List the pharmacological measures used to treat constipation
- Stool softener
- Laxatives (promote/ stimulate bowel movement, add bulk)
List the type of laxative that should not be used in Opioid Induced Constipation
Bulk forming. Opioids prevent peristalsis of the increased bulk which worsens abdominal pain and can contribute to bowel obstruction
List the CI for suppositories/ enemas
Low white blood cell or platelet counts because of the risk of infection or bleeding when these products are used.
Describe the pathophysiology of mucositis
o Five-stage nonlinear process that occurs rapidly and concurrently along the alimentary tract
1) Initiation: Chemotherapy or radiation causes direct toxicity to cells, tissues, and vasculature via generation of oxidative stress and reactive oxygen species. In addition, an increase in vascular permeability by inflammatory mediators allows local accumulation of toxic drugs.
2) Upregulation with generation of messengers: 4–5 days after treatment, reactive oxygen species damage DNA, leading to epithelial cell death. Extent of damage to tissues is based on the rate of oral epithelium proliferation. Concurrently, nuclear factor-ĸB is activated by chemotherapy or radiation, causing gene upregulation, which leads to the production of proinflammatory cytokines and expression of adhesion molecules, ultimately resulting in tissue damage, activation of the cyclooxygenase-2 pathway, angiogenesis, and apoptosis.
3) Signaling and amplification: Signaling mediators released after initial injury include pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) as part of positive feedback loops that that indirectly increase and extend damage to the mucosa. Biology is altered, but tissue will still appear normal.
4) Ulceration: Most symptomatic phase that peaks when blood counts reach their nadir, about 7 days after treatment. Prior injury to basal epithelial cells causes atrophy and mucosal breakdown. Oxidative stress leads to inflammatory infiltrates, and bacterial cell wall materials (gram positive, gram negative, and anaerobes) activate macrophages, further increasing the production of pro- inflammatory cytokines.
5) Healing: Begins with white blood cell count recovery at ~day 12–16. Epithelial cells begin to proliferate and differentiate, and local flora return. Because of continued angiogenesis, patients are at an increased risk of mucositis in the future.
Summarised vers:
●Initiation – Chemotherapy and radiation therapy damage both DNA and non-DNA targets, both as a direct effect and mediated through reactive oxygen species.
●Upregulation and generation of messenger signals – The initial injury activates the transcription factor nuclear factor-kappa B, leading to the production of a variety of biologically active proteins, including proinflammatory cytokines.
●Signaling and amplification – As proinflammatory cytokines accumulate, they damage surrounding tissues directly, and the effect is amplified via feedback loops. This phase precedes the development of overt clinical mucositis.
●Ulceration and inflammation – Loss of mucosal integrity results in clinically painful lesions and allows secondary bacterial colonization.
●Healing – Mucositis generally is self-limited, and healing begins once the tissue insult is withdrawn.
Describe the severity grading for mucositis
Grade 1: Redness, soreness/ mild asymptomatic, no intervention required
Grade 2: Ulcer, can still eat solid food; Moderate Pain leading to modified diet
Grade 3: Ulcer, only able to take liquid food; Severe pain that interfere with PO intake
Grade 4: Ulcer, not able to intake any food; life-threatening
List the risk factors for Mucositis (many many)
1) Patient-related factors
* Autoimmune disorders
* Diabetes
* Female (5-FU induced)
* Caucasians are at greater risk than African Americans.
* Genetic predisposition to tissue damage -> Deficiency in genes that produce enzymes responsible for metabolizing chemotherapy
* Folic acid or vitamin B12 deficiency
2) Treatment-related factors (Majority)
* Chemotherapy
o Varies by agent and regimen
o S-phase specific agents have highest risk (drugs that target S-Phase)
o Duration, dose intensity, schedule
o Prolonged or repetitive lower doses result in higher risk than bolus doses.
o Risk increases with number of cycles.
o Risk increases when clearance of chemotherapy is delayed by renal or hepatic impairment.
o Previous therapies toxic to mucosa
o Risk increases with previous episodes of mucositis.
* Radiation
o Risk of mucositis increases when radiation is added to chemotherapy.
o Risk is dependent on radiation source, dosage, dose intensity, and volume of mucosa irradiated -> E.g if radiate the throat area for throat cancer, risk of mucositis is higher; if radiate prostate, risk of mucositis is lower because it is further away.
3) Smoking and alcohol consumption increase risk.
4) Risk is higher in the presence of xerostomia and infection
List the chemotherapy agents more specific for S-phase and hence increases risk of mucositis
1) Topoisomerase inhibitor (Irinotecan, Topotecan)
2) Antimetabolites (MTX, Pemetrexed, 5-FU, -bines, Mercaptopurine, Thioguanine)
What are the goals of treatment for mucositis? (3)
o Prevent or decrease severity of mucositis.
o Manage pain and other associated symptoms.
o Prevent chemotherapy delays or dosage reductions.
List the medicated mouthwashes to be taken before food and the purpose of taking before food in the treatment of mucositis
- Mylocaine, Morphine Sulfate
Taken before food to relieve pain
List the medicated mouthwashes to be taken after food and the purpose of taking after food in the treatment of mucositis
Oracare
To kill germs
State the type of mouthwashes to be avoided in mucositis and why
Alcohol based mouthwash. Alcohol has a drying effect and might cause more xerostomia (mouth dryness) resulting in mucositis
List the prevention and treatment measure for HSCT patients for mucositis. Include doses if any
Prevention:
- Palifermin (IV 60 mcg/kg/day for 3 consecutive days before and after myelotoxic therapy)
- Low Level Laser Therapy (LLLT) after high-dose chemotherapy ± Total Body Irradiation (TBI)
- Oral Hygiene
- Oral Cryotherapy (Ice chips)
o After bolus 5-FU or
o 30mins before, during and up to 1-2 hours past infusion with high dose Melphalan
Treatment:
- Patient controlled analgesia with morphine for pain
List the prevention and treatment measure for Head and Neck Cancer patients with mucositis include doses if any
Prevention:
- Benzydamine mouthwash after radiation < 50 Gy or chemoradiation
- Low Level Laser Therapy after radiation
- Oral Hygiene
- Oral Cryotherapy (Ice chips)
o After bolus 5-FU
Treatment:
- 0.2% Morphine mouthwash for pain
- Systemic opioid for pain
List the CTCAE grading for CID
1: Loose stool < 4 times a day above baseline
2: Loose stool 4-6 times a day above baseline + Limits activities of daily living
3: Increase of 7 or more stools a day above baseline + Hospitalisation needed, and self-care is limited
4: Life threatening diarrhea, urgent intervention needed
MOA of NK-1 antagonist in preventing CINV
Inhibits substance P from binding to NK-1 receptors. Attenuates vagal afferent signals (augments antiemetic effect of 5HT3 antagonists) and exert antiemetic effect
MOA of 5HT3 antagonist in preventing CINV
Block 5HT-3 receptors peripherally in the gastrointestinal tract and centrally in the medulla
MOA of Olanzapine in preventing CINV
Antagonistic effects on mulitple receptors involved in CINV: Histamine, dopamine, Serotonin, Cholinergic
MOA of Dopamine antagonist (e.g Metoclopramide) in preventing CINV
Blockade of dopamine receptors in the chemoreceptor trigger zone; stimulation of cholinergic activity in the gut, increasing (forward) gut motility; and antagonism of peripheral serotonin receptors in the intestines.
DDIs of NK-1 antagonist (4) State which CYP enzymes they affect
- Steroids
- Warfarin (Aprepitant, INR will decrease)
- Benzodiazepines (increase benzodiazepine concentrations due to reduced metabolism)
- Certain chemotherapy eg Ifosfamide (decreases metabolism of ifosfamide)
It is a CYP3A4 inhibitor (A + N), CYP2C9 inducer (A)
Dosing of NK-1 antagonists (2)
- Aprepitant (Emend®) 125 mg PO day 1, 80 mg PO days 2-3
- Netupitant 300mg (in combination with 5HT3 antagonist Palonosetron 0.5mg) (Akynzeo®) PO day 1 -> requires single dose only
Dosing of Olanzapine
- 5mg – 10mg OD, consider lower doses (2.5mg OD) for elderly
Dosing of Dexamethasone
- IV/PO 12mg OD D1, IV/PO 8mg OD D2 onwards for highly emetogenic regimens
Dosing of 5HT3 antagonists (2)
- IV/PO Ondansetron 8-16mg OD Day 1, IV/PO Ondansetron 8mg BD Day 2 onwards (max 16mg/dose)
- IV/PO Granisetron 1mg OD Day 1, IV/PO Granisetron 1mg OM Day 2 onwards
MOA of Benzodiazepine
- Binds to benzodiazepine receptors on the postsynaptic GABA neuron to enhance inhibitory effect of GABA
- Leads to sedation, reduction in anxiety, and possibly depression of the vomiting centre
Dosing of benzodiazepines for CINV (2)
- PO alprazolam 0.5-1mg/PO lorazepam 0.5-2mg on the night before treatment and then 1-2 hours before chemotherapy begins
MOA of Haloperidol (Butyrophenones)/ Phenothiazines (prochlorperazine, chlorpromazine, promethazine) in preventing CINV
Block dopamine receptors in the chemoreceptor trigger zone
State the classes of drugs used for high risk CINV and regimen
Acute: NK-1 + 5HT3 + DEXA +- Olanzapine
Delayed: Dexa (D2-4) or Olanzapine if olanzapine was used + NK1 (if Aprepitant)
State the classes of drugs used for moderate risk CINV and regimen
Acute: 5HT3 + DEXA
Delayed: Dexa (D2-4)
State the classes of drugs used for low risk CINV and regimen
5HT3 or DEXA or DOPA (Metoclopramide)
State the CINV antiemetics that have potential to cause QT prolongation
Olanzapine, 5HT3 antagonist, Metoclopramide, Benzo
