GI Medications Antiemetic Agents PDF

GI Medications Anti-Emetics Debra Forzese, Pharm. D. Neurotransmitter Receptor Sites in Vomiting NEUROTRANSMITTER RECEPTOR SITE M1 MUSCARINIC D2 DOPAMINE H1 HISTAMINE 5 HT-3 SERATONIN NK1 SUBSTANCE P Seratonin 5-HT3 Antagonists Seratonin 5-HT3 Antagonist Agents Ondansetron (Zofran) Granisetron (Kytr...

GI Medications Anti-Emetics Debra Forzese, Pharm. D. Neurotransmitter Receptor Sites in Vomiting NEUROTRANSMITTER RECEPTOR SITE M1 MUSCARINIC D2 DOPAMINE H1 HISTAMINE 5 HT-3 SERATONIN NK1 SUBSTANCE P Seratonin 5-HT3 Antagonists Seratonin 5-HT3 Antagonist Agents Ondansetron (Zofran) Granisetron (Kytril) Dolasetron (Anzemet) Palonosetron (Aloxi) 5-HT3 Antagonists Block serotonin on GI vagal nerve terminals and in chemoreceptor trigger zone (peripheral and central activity) Powerful antiemetic effects restricted to vagal stimulation (post-op) and chemotherapy Most effective agents for treatment of chemotherapy induced and post operative nausea/vomiting Extensive hepatic metabolism Ondansetron Indications Cancer chemotherapy induced nausea/vomiting Postoperative nausea and/or vomiting Radiation associated nausea and vomiting Off label use – prevention of nausea and vomiting associated with pregnancy Ondansetron Dosing Adult – avoid IV doses over 16 mg due to potential for QT prolongation, avoid in patients with congenital long QT syndrome Pediatric Renal impairment – no dose adjustment Hepatic impairment – severe impairment reduce dose Ondansetron Pharmacokinetic/Pharmacodynamic Factors Onset of action about 30 minutes Half life 3-6 hours Hepatic metabolism Administered oral, IM, IV Ondansetron – Adverse Effects Constipation – intestinal obstruction occurs rarely Headache – rapid, severe Dizziness Hypersensitivity – urticaria, angioedema, anaphylaxis QT prolongation Elevated liver enzymes - transient Cardiac – atrial fibrillation, palpitations, coronary artery spasm Ondansetron Warnings Seratonin syndrome – increased risk when used with other serotonergic agents such as SSRIs, some fatal cases o Symptoms include agitation, anxiety, disorientation, tremors, muscle rigidity, akathisia, HTN, tachycardia, hyperthermia, diaphoresis, shivering, vomiting, diarrhea, arrhythmias o https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865832/ Ondansetron Drug Interactions Amiodarone – enhances QTc prolonging effect of ondansetron QT-prolonging agents – additive risk Serotonergic agents – ondansetron can increase risk of serotonin syndrome Ondansetron Pregnancy – data inconsistent, may be considered for treatment of severe or refractory nausea/vomiting when preferred agents not effective, current guidelines suggest use prior to 10 weeks gestation be individualized Breastfeeding- according to manufacturer, decision to breastfeed during therapy should consider risk of infant exposure, benefits of breastfeeding to the infant, and benefits of treatment to patient Ondansetron Monitoring ECG – if high risk for QT interval prolongation (low K+ or Mag), other meds that prolong QT interval Magnesium, potassium levels Signs/symptoms of serotonin syndrome Hypersensitivity Decreased bowel activity Cardiac ischemia Neurokinin Receptor Antagonists Neurokinin Receptor Antagonists Agents (NK 1) Aprepitant (Emend) Netupitant (combined with palonosetron) Rolapitant (Varubi) Neurokinin Receptor Antagonists Antiemetic effects in delayed nausea and improve efficacy of standard antiemetic regimens for those receiving multiple cycles of chemotherapy Possess anxiolytic, antidepressant, and antiemetic properties Aprepitant Indications IV - post operative nausea/vomiting, prevention of chemotherapy induced nausea and vomiting Oral – prevention of chemotherapy induced nausea and vomiting, has not been studied for management of existing nausea/vomiting, chronic continuous use not recommended Aprepitant Dosing Adult Pediatric Renal impairment – no dose adjustment Hepatic impairment – use with caution in severe impairment Aprepitant Mechanism of Action Prevents acute and delayed vomiting by inhibiting substance P/neurokinin 1 receptor, augments antiemetic activity of 5-HT3 receptor antagonists and corticosteroids to inhibit acute and delayed phases of chemotherapy induced vomiting Aprepitant Pharmacokinetic/Pharmacodynamic Factors Extensively metabolized via CYP3A4, CPY1A2, CYP2C19 Half life 9-13 hours (IV and oral) Excreted primarily via metabolism Dose dependent inhibitor and inducer of CYP3A4 Aprepitant Adverse Effects Hematologic – neutropenia – higher incidence in children/adolescents CNS – fatigue – higher incidence in adults CV – flushing, hypotension GI – abdominal pain, diarrhea Aprepitant Warnings Hypersensitivity reactions – anaphylaxis Avoid use in pediatric patients less than 6 kg Aprepitant Drug Interactions Dose dependent inhibitor and inducer of CYP 450 CYP3A4 Induces CYP2C9 Common interactions include benzodiazepines, ketoconazole, dexamethasone(requires dose reduction when administered with aprepitant) Monitor patients on oxycodone (increased levels) and hormone contraceptives (contraceptive failure) Aprepitant Pregnancy – avoid use, data lacking Breastfeeding – according to manufacturer, decision to breastfeed during therapy should consider risk of infant exposure, benefits of breastfeeding to infant, benefits of treatment to mother (injectable formulation contains ethanol) Aprepitant Monitoring Monitor for hypersensitivity reaction Monitor patients with severe hepatic impairment for adverse effects Antipsychotics used as Antiemetics Antipsychotic Agents used as Antiemetics Phenothiazines Prochlorperazine (Compazine) Promethazine (Phenergan) Thiethylperazine (Torecan) Olanzapine (Zyprexa) Butyrophenones Droperidol (Inapsine) Antipsychotics Used for their antiemetic and sedative properties, different classes of antipsychotics o Antiemetic properties of phenothiazines (promethazine) mediated through inhibition of dopamine and muscarinic receptors o Antiemetic properties of butyrophenones (droperidol) due to central dopaminergic blockade Sedation from antihistamine activity Antipsychotics - Promethazine Indications Acute nausea and/or vomiting Off label – pregnancy associated nausea and vomiting Promethazine Dosing Adult – avoid IV, IM, subQ; use oral or rectal short term (48-72 hours) for nausea/vomiting Pediatric Renal impairment – no dose adjustment Hepatic impairment – no dose adjustment Promethazine Mechanism of Action Antidopaminergic, antihistamine, anticholinergic activity Promethazine Pharmacokinetic/Pharmacodynamic Factors Formulations – oral, rectal, IM/IV Onset of action for oral/IM 20 minutes, IV 5 minutes Half life for IM 10 hours, IV 9-16 hours, suppositories 16-19 hours Excretion via urine, feces Promethazine Boxed Warnings Avoid use of promethazine in pediatric patients younger than 2 years because of potential for fatal respiratory depression May cause serious tissue injury when injected, including gangrene, regardless of the route of administration Promethazine – Adverse Effects CNS – confusion, sedation, dizziness, motor dysfunction Extrapyramidal symptoms – akathisia, drug induced parkinsonism, tardive dyskinesia Anticholinergic - blurred vision, xerostomia, constipation, urinary retention CV – arrhythmias, hypotension Neuroleptic malignant syndrome Hepatic – cholestatic jaundice Hypothermia/hyperthermia Promethazine - Cautions Altered cardiac conduction (potentially life -threatening arrhythmias) Photosensitivity Narrow angle glaucoma may be exacerbated Avoid use in patients with compromised respiratory function Use cautiously in patients with seizures Recommendation to eliminate all injectable promethazine from hospitals per ISMP – to eliminate risk of serious tissue injuries and amputations from inadvertent arterial injection or IV extravasation of injectable promethazine Promethazine Drug Interactions CNS depressants – promethazine may intensify, increase, prolong sedative action of CNS depressants (sedatives, narcotics, alcohol) Anticholinergics – potential additive effects MAO inhibitors – increased risk of EPS Promethazine Drug interactions CNS depressants – promethazine may intensify, increase, or prolong sedation from other CNS depressants Anticholinergics – use cautiously, effects additive Promethazine Pregnancy – category C Breastfeeding – potential for serious adverse effects in the breastfed infant, manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue drug, taking into account importance of treatment to the mother Promethazine Monitoring If used parenterally monitor for tissue damage Anticholinergic effects CNS depression Substituted Benzamides Substituted Benazamide Agents Metoclopramide (Reglan) Trimethobenzamide (Tigan) Trimethobenzamide Mechanism of action – blocks emetic impulses to central vomiting center Indications – treatment of post-operative nausea/vomiting, treatment of nausea associated with gastroenteritis Administration – oral, IM Renal impairment – reduce dose or increase dosing interval Hepatic impairment – avoid use Warnings – CNS effects, EPS, hepatotoxicity Trimethobenzamide Pediatrics - Use in pediatrics strongly discouraged due to risk of EPS, CNS side effects; use of IM formulation in pediatric patients contraindicated H1 Antihistamines and Anticholinergics H1 Antihistamines and Anticholinergics Dimenhydrinate Meclizine antihistamine, anticholinergic activity antihistamine, little anticholinergic activity Promethazine inhibit dopamine/muscarinic receptors antihistamine Scopolamine antagonize muscarinic receptors, high anticholinergic activity Scopolamine (Transderm- Scop) Indications Prevention of nausea and vomiting associated with motion sickness Postoperative nausea and/or vomiting prevention (recovery from anesthesia or opiod analgesia and surgery) Scopolamine Patch Dosing Adult- transdermal patch applied behind ear at least 4 hours prior to required antiemetic effect for use up to 72 hours, may use 2 patches if needed for motion sickness Pediatric – may be more susceptible to anticholinergic adverse effects Renal impairment – no dose reduction Hepatic impairment – no dose reduction Scopolamine Patch Mechanism of action Competitively inhibits post-ganglionic muscarinic receptors for acetylcholine and acts as a nonselective muscarinic antagonist, producing peripheral antimuscarinic effects and central sedative, antiemetic, amnestic effects Scopolamine Patch Pharmacokinetic/Pharmacodynamic Factors Onset of action – 6-8 hours Duration of activity – 72 hours Hepatic metabolism Half life – 9.5 hours Scopolamine Patch Adverse effects Anticholinergic – urinary retention, xerostomia, blurred vision CNS – sedation Withdrawal – muscarinic receptor sensitization, rebound overstimulation, from prolonged use Scopolamine Patch Warnings/Cautions Transdermal patch – may contain conducting metal (aluminum), remove patch prior to MRI Use with caution in patients with open angle glaucoma, may increase intraocular pressure Scopolamine Patch Drug Interactions CNS depressant medications – additive sedation Medications with anticholinergic activity – additive effects Scopolamine Patch Pregnancy – avoid use in pregnant patients with severe preeclampsia Breastfeeding – may cause maternal sedation and adversely affect milk supply with repeated doses, other agents preferred Monitoring o Body temperature, heart rate, urinary output, intraocular pressure, mental alertness Cannabinoids Cannabinoid Antiemetics Dronabinol (Marinol) Dronabinol FDA schedule II Indications o Chemotherapy induced nausea and vomiting – in patients who have failed to respond to conventional antiemetic agents o Anorexia in patients with AIDS Dronabinol Dosing Adult Pediatric Renal impairment – no dose adjustment Hepatic impairment – no dose adjustment Dronabinol Mechanism of Action Exert antiemetic properties through interactions with centrally located CB1 receptors and 5-HT3 receptors in the dorsal vagal complex which mediates emesis Dronabinol Pharmacokinetic/Pharmacodynamic Factors Onset of action – 30 -60 minutes Duration – 4-6 hours Extensive first pass hepatic metabolism Therapeutic index is wide Dronabinol Adverse effects CNS – euphoria CV – facial flushing, palpitations, tachycardia GI – abdominal pain Hepatic – increased liver enzymes Dronabinol Warnings/Cautions May cause possible hypertension, syncope CNS – can exacerbate depression, mania, schizophrenia GI – new or worsening paradoxical nausea/vomiting, abdominal pain Hypersensitivity Seizures Patients with history of substance abuse – may be more likely to abuse dronabinol Dronabinol Drug interactions Drugs that inhibit or induce CYP 450 2C9 and 3A4 can affect blood level of dronabinol Dronabinol Pregnancy – avoid use, may result in fetal harm Breastfeeding – use not recommended Monitoring o Watch for tachycardia, orthostasis, behavioral changes