Antiemesis Management In Cancer Therapy - Part 2

ANTIEMESIS MANAGEMENT IN CANCER THERAPY - PART 2 Dr. Leiva DOPAMINE RECEPTOR ANTAGONISTS drowsinessconstipation hypotension Postma 2516mg gtcanymouthidizzing • *Olanzapine (Zyprexa) – Used in treatment and prophylaxis; including here for completeness • Metoclopramide (Reglan) Notemyeffectivefor was • Promethazine (Phenergan) NI • Prochloperazine (Compazine) • Haloperidol (Haldol)soft prolongation GoMostlyforPIwirefactoryNIV Pharmacology: • Act on dopaminergic receptors at the CTZ Prochlorperazine DOPAMINE RECEPTOR ANTAGONISTS • Effective for low and moderately emetogenic • Half-life is 3-8 hours depending on route • PO preferred route Promethazine Metoclopramide • Most effective single agent until 5-HT3 antagonists; not as highly recommended due to irreversible TD • Effective in nausea related to delayed gastric emptying/constipation Haloperidol: • Used more in breakthrough and refractory cases of CINV • Prolonged QTc intervals and EPS limit its use Common: Serious: Sedation, hypotension (if prochlorperazine IV given quickly), anticholinergic effects Acute dystonias, neuroleptic malignant syndrome [rare], and so tardive dyskinesias DOPAMINE RECEPTOR ANTAGONISTS - ADRS BENZODIAZEPINES • Lorazepam (Ativan) - Reversal agent Flumazenil – PO, SL (PO tablets under tongue), IV Eton • Pharmacology: – Binds GABA-BZD receptor; exerts tranquilizing action on CNS – Half-life for oral ~12 hours – Has no intrinsic antiemetic properties but valuable adjunct to treat – Anxiety related CINV • ADRS: – Confusion, euphoria, paradoxical excitation, physical dependence, over sedation • Ancient, evolutionarily conserved, and ubiquitous lipid signaling system found in all vertebrates • Involved in broad number of physiological and pathophysiological processes T H E H U M A N E N D O C A N N A B I N O I D S Y ST E M ( E C S ) CANNABINOIDS - VARIOUS SOURCES I 2 Adapted from Mayo Clinic Proceedings 2019 941840-1851DOI: (10.1016/j.mayocp.2019.01.003) 3 SYNTHETIC CANNABINOIDS • Nabilone (Cesamet) – Schedule II (CRAY!) • Dronabinol (Marinol) – Schedule III (stored in the fridge prior to dispensing) • Pharmacology – Synthetic cannabinoids receptor agonist-not fully understood; however similar to marijuana’s effects on the brain • ADRS – Drowsiness, vertigo, euphoria, postural hypotension, psychosis, anxiety CANNABIS – “A TALE OF TWO SUBSPECIES” “Weed” Hemp • Pharmacologically active - Phytocannabinoids and terpenoids are produced in secretory cells inside glandular trichomes that are most highly concentrated in unfertilized female flowers prior to senescence • >120 phytocannabinoids and terpenoids identified • Sativa dominant strains are purported to be “activating” • Indica dominant strains are purported to be “sedating” or cause ”couch lock” MAJOR CANNABINOIDS – THE 411 ON 420 Intoxicating • Used for acute pain, appetite stimulation, sleep, anxiety/stress, nausea, muscle spasticity, neuropathic pain, glaucoma symptoms, etc • Most abundant cannabinoid in weed plants. Non-intoxicating • Used for seizure disorders, anxiety, sleep, inflammation, chronic pain, arthritis, nausea, etc • Major phytocannibinoid in hemp and weed plants MINOR CANNABINOIDS Non-intoxicating • THCa (tetrahydrocannabinolic acid) – Precursor to activated THC but only mild or minimal psychoactivity • CBN (cannabinol) – Breakdown product of THCa – Sedative effects • CBG (cannabigerol) • Used for pain, sleep, muscle spasticity, psoriasis, glaucoma symptoms, etc. • The “stem cell” cannabinoid in hemp and weed plants PHA RM A C OL OG Y / PH AR M AC O KIN ET IC S y shouldbecombinewith Pharmacology Boosttheefficacy • CBD – non-competitive, negative, allosteric modulator of CB1 receptor and numerous other receptors, antagonizes THC effects on CB1 • CBG – weak partial agonist for CB1 and CB2 receptors; may partially antagonize THC effects on CB1 • THC - CB1 receptor antagonist and CB2 receptor partial agonist Pharmacokinetics • CBD • Terminal half-life 31+ 4 hours • Highly lipophilic; poor oral bioavailability • Metabolized by CYP2C9, CYP2C19, and CYP3A4; inhibits CYP2C19 and p-glycoprotein mediated drug transport • THC • Terminal half-life 22 hours • Highly lipophilic; poor oral bioavailability • Metabolized by CYP2C9, CYP2C19, and CYP3A4; inhibits CYP1A1, 1A2, 1B1 SAFETY AND TOXICITY PROFILE Reported ADRs – Mostly associated with THC derivatives/concentration II atEgm • Somnolence • Tachycardia (higher doses of THC) • Intoxication or impairment • Paranoia or temporary psychosis (associated with higher doses of THC) • Increased appetite (“munchies”) • Agitation • Hyperemesis (cyclic vomiting syndrome) • Dry mouth • dizziness • Limited reports of hepatoxicity (Epidiolex but trial combined antiseizure medications) Overdose • LD 50 - 130mg/kg THC in dogs and monkeys – human weighing 65 kg would require a dose of 8.45kg. • CBD Therapeutic Index – 1,000:1 • No fatal overdoses have been reported CBDBappetite DOSING GUIDE Medical goal = lowest dose of THC for symptom control and functional improvement Self titrate to lowest THC dose (max benefit & min ADE) “Start low, go slow and stay low ” No real dosing guidelines for CBD • Higher ratio CBD/CBG (CBD rich) allows for lower dose of THC Typically tolerance to adverse effects but NOT to benefit • New information regarding efficacy in mild vs. mod/severe symptom management THC start = 2.5 mg  5mg  7.5mg  10mg Average dose cannabis = 1-3 g/day (5% use > 3g / day) wontto Don't recommend j ROUTES OF ADMINISTRATION Issue Smoking/Vaporization Onset (min) 5-10 60-180 15-45 Variable Duration (h) 2-4 6-8 6-8 variable Pros Rapid action, Advantage for acute or episodic symptoms Less odor, convenient and discreet, good for chronic disease Fast onset, discreet, good for acute or episodic symptoms safer than smoking Less systemic, good for localized symptoms Cons Dexterity required, may aggravate Titration underlying lung conditions, potential harm challenges due to to lungs delayed onset Expensive, same products not always available Only local effects t Oral Oromucosal Adapted from MacCallum C, Russo E."Practical Considerations in Medical Cannabis Administration and Dosing". EuropJ Intl Med 2018 Topical NON-SYNTHETIC CANNABINOIDS • Legal in CA both for recreational and medicinal use – THC (Tetrahydrocannabinol) vs. CBD (Cannabidiol) – Patients should make sure they trust the source NOW FOR THE GUIDELINES!! 901 takeinmorningw food 3090 4 Better option t PATIENT CASE - TK • TK is a 34 y/o cisgender female starting on 4 cycles of dose dense Adriamycin Cytoxan (AC) Following AC, and then she will receive 4 cycles of paclitaxel for Stage Ilb TNBC. • She reports a remote h/o of motion sickness as a child and was diagnosed with generalized anxiety disorder at 17 y/o. She does not smoke and reports approximately 7 ETOH drinks per week. alone Tainostron **Please Answer These Questions Before Coming to Class: 1. What emetogenicity risk is associated with the 4 cycles of AC? 2. Independent of her chemotherapy, what risk factors does she have (if any) for experiencing chemotherapy induced nausea and vomiting? 3. Does her chemotherapy have the same emetogenic risk for all 8 cycles? 4a. If she experienced nausea the day before her 2nd cycle of AC, what type of CINV would you be concerned about? 4b. How would you adjust her antiemetic regimen? Ativen PATIENT CASE - PD **Please Answer These Questions Before Coming to Class: • PD is a 62 y/o cisgender male due to receive weekly carboplatin for 6 weeks concurrent with radiation (XRT) for Stage IVb squamous cell carcinoma of the oropharynx. • PD has a 30 PPD history and consumes 23 ETOH per month. He reports having meniere’s disease for 4 years and takes meclizine for particularly severe spills. Delayed Breakthroght Moderate 1. What emetogenicity risk is associated with his carboplatin regimen? 2. Independent of his chemotherapy, what risk factors does he have (if any) for experiencing chemotherapy induced nausea and vomiting? 3a. If he experienced nausea and 2 bouts of emesis on Day 3 of his 1st cycle, what type of CINV do you think PD is dealing with? 3b. How would you adjust his antiemetic regimen? oxidetaday up olanzapineAl 21319 Adddata NCCN GUID ELI NES (ORAL ANTI CANCER EMETOGENIC IT Y) Fyi As a reminder please make sure that you know the level for all of the parenteral and oral agents we cover!! ORAL ANTICANCER – EMESIS PREVENTION NCCN GUID ELI NES ( BREAKTHROUGH TREATMENT) I Gt N C C N G U I D E L I NE S ( A NT I C I PAT O R Y E M E S I S T RE AT M E N T ) NCCN Guidelines (Antiemesis for RINV) Fyi Antiemetic Guideline Clinical Pearls Antiemetic Guideline Clinical Pearls sedation no 2Sms startmostlyat Antiemetic Guideline Clinical Pearls PERCEPTION VS. REALITY Highly Emetogenic Chemo Moderately Emetogenic Chemo Percentage of patients Percentage of patients 62 53 34 53 39 37 33 17 22 24 13 13 ACUTE NAUSEA ACUTE VOMITINGDELAYED NAUSEA MD/RN Prediction DELAYED VOMITING ACUTE NAUSEA Patient Experience 15 13 ACUTE VOMITING MD/RN Prediction Grunberg S. Cancer. 2004;100:2261-2268 28 24 DELAYED NAUSEA Patient Experience DELAYED VOMITING