Nausea & Vomiting Treatment 2024 PDF

# Nausea & Vomit ## Universidad Autónoma de Guadalajara School of Medicine **We Make Doctors** ## Learning Objectives * **Define Nausea**, vomiting, sialorrhea, arcade, and kinetosis, and identify their differences * Identify the main etiologies of nausea and vomiting, and relate them to the pat...

# Nausea & Vomit ## Universidad Autónoma de Guadalajara School of Medicine **We Make Doctors** ## Learning Objectives * **Define Nausea**, vomiting, sialorrhea, arcade, and kinetosis, and identify their differences * Identify the main etiologies of nausea and vomiting, and relate them to the pathophysiological pathways * Acknowledge the structure, pharmacokinetic & pharmacodynamic properties, as well as the specific medical indications of drugs used in the treatment of nausea and vomiting. * Serotonin antagonists * Dopamine antagonists * Muscarinic antagonists * Neurokinin antagonists * Antihistamine drugs * Cannabinoids ## Definitions * **Nausea:** Unpleasant and imminent feeling of vomiting. Cutaneous pallor, sialorrhea. * **Vomiting:** Vomiting, also called emesis, is the violent and spasmodic expulsion of stomach contents up through the esophagus and out of the mouth. It is a reflex act usually preceded by nausea. Diaphoresis, involuntary contraction of the abdominal and pharyngeal muscles, and tachycardia. * **Sialorrhea:** Increased secretion of saliva that flows through the mouth. * **Arcade:** Violent movement of the stomach and esophagus to induce vomiting. * **Kinetosis:** Motion sickness. Fatigue, loss of balance, nausea, and vomiting. ## Vomiting is a Defensive Response Vomiting is a defensive response whose purpose is to free the body of toxic or irritating materials. * The poisons * The bacterial toxins * Cytotoxic drugs * Mechanical distention They trigger the release of mediators, such as 5-HT, by enterochromaffin cells in the lining of the digestive tract. These transmitters activate signals in the vagal afferent fibers. ## Epidemiology * 25% of people visit the family doctor due to nausea. It is more common in people between the ages of 15-24 years and is less frequent in children and the elderly. * Approximately 75% to 80% of pregnant women experience a variable degree of nausea, vomiting, and/or sialorrhea at the beginning of pregnancy. * The prevalence of nausea in each trimester was 63.5%, 33.8%, 26.2%. * The prevalence of vomiting in each trimester was 29.3%, 22.1%, 14.1%. * Nausea and vomiting in the postoperative period (PONV) as one of the most frequent complications with an incidence ranging between 4.6% and 49.0%. * In 1191 patients over 15 years of age, the incidence of PONV found was 8.1% (7.8% for nausea and 3.6% for vomiting). Its presentation was especially related to female sex, laparoscopic surgery, and anesthesia time greater than 180 minutes. * Nausea and vomiting induced by chemotherapy are one of the most distressing acute side effects of cancer treatment; they occur in up to 80% of patients. * Other causes for nausea and vomiting include: * Serious metabolic disorders * Malnutrition and anorexia. * Impairment of the patient's mental and physical state. * Esophageal tears * Fractures * Dehiscence of wounds. * Abandonment of a potentially useful and curative antineoplastic treatment. ## Causes of Nausea and Vomiting | Cause | | Cause | | Cause | |---|---|---|---|---| | **Intraperitoneal** | | **Extra-peritoneal** | | **Pharmacotherapy/other Metabolic Disorders** | | Obstructive disease | | Cardiomyopathies | | Drugs | | Pylorus | | Myocardiopathie | | Chemotherapies (Antineoplastic, Antibiotics) | | Duodenal | | Infraction | | Oral hypoglycemic agents | | Colon | | Vestibular disease | | Oral contraceptives | | Enteric infections | | Kinetosis | | Metabolic disorders (Uremia, Ketoacidosis, Pregnancy) | | Inflammatory bowel disease | | Intracranial diseases | | Toxins | | Motility dysfunctions | | Cancer | | Hepatic insufficiency | | | | Hemorrhages | | Ethanol | | | | Abscess | | Radiation therapy | | | | Hydrocephaly | | | | | | Psychiatric disorders | | | | | | Anorexia & bulimia | | | | | Depression | | | | | Psychogenic vomit | | ## Diagram of Causes The diagram shows the various causes of nausea and vomiting, broken down by the affected area of the body. * **Chemoreceptor Trigger Zone/ Area Postrema** * **Drugs:** Chemo agents, Anesthesia (Opoids, NSAIDS, Aspirin), Antigout drugs (Cardiovascular agents, Diuretics, Antibiotics, Nicotine, Alcohol, Hypervitaminosis), Digoxin, Antiarrhythmics, Anti HTN, Bb/CCB * **Toxins:** Bacteria, Viral * **Metabolic:** Uremia, DKA, Hypercalcemia, AIP, Addison's disease, Hyperthyroidism * **GI Tract** * **Stretch:** Obstruction, Constipation, Gastroparesis * **Gastric Irritants/mucosal disruption:** Gastritis/PUD/GERD * **Foods** * **IBS** * **Pancreatitis** * **Hepatitis** * **Mesenteric ischemia** * **Malignancy** * **Cortex/ CNS:** * **Migraine** * **Emotional response** * **Stress** * **Pain** * **Increased ICP:** * **Malignancy** * **Hemorrhage** * **Infarction** * **Meningitis** * **Abcess** * **Hydrocephalus** * **Pseudotumor cerebri** * **Vestibular** * **Motion sickness** * **Meniere disease** * **Tumors** * **Labyrinthinitis** * **BPPV** * **Vestibular neuritis** ## Vomiting Center The diagram shows the brain structures involved in vomiting. Note the various afferent fibers involved. * **Central Nervous system:** Cortex, Thalamus, Hypothalamus, Meninges * **Gastrointestinal Tract and Heart:** * **Vestibular System:** * **Chemoreceptor Trigger Zone (Area Postrema):** * **Vomiting Center (Nucleus of Tractus Solitarius):** **The Vomiting Center:** The vomiting center can be activated by afferent fibers arising from the gut, CTZ, cerebral cortex, or vestibular apparatus. **Vomiting Center:** Initiates vomiting; this center coordinates a complex series of events involving pharyngeal, GI, and abdominal wall contractions that lead to the expulsion of the gastric contents. ## Vomiting The vomiting process can be broken down into several phases: * **Pre-expulsion:** Gastric relaxation and retro-peristalsis. * **Retch:** Rhythmic action of the respiratory muscles that precedes vomiting and consists of contraction of the abdominal and intercostal muscles and the diaphragm against a closed glottis that elevates the intra-gastric pressure. * **Expulsion:** Intense contraction of the muscles of the abdomen and relaxation of the high esophageal sphincter. A phasic and simultaneous contraction of the pylorus prevents the caudal propulsion of the gastric contents, forcing the opening of the lower esophageal sphincter, after the simultaneous relaxation of the body and gastric fundus. ## Diagram of the Vomiting Center * **Controls:** Salivation, Respiratory rate, Pharyngeal, GI and abdominal muscle contractions * **Enterochromaffin cells of the GI tract:** Serotonin release * **Vomiting center:** * 5-HT₃ receptors * NK₁ receptors * Dopamine receptors * **Afferent fibers of the vagus nerve:** **Chemoreceptor Trigger Zone:** * 5-HT₃ receptors * NK₁ receptors * Dopamine receptors ## Treatment * Conduct a focused history and physical examination to identify the etiology of nausea and vomiting * Correct the metabolic disorders * Treat the underlying disease * Administer antiemetic therapy based on etiology ## Antiemetic Therapy * Choose the parenteral route if acute onset of recurrent vomiting * Take into consideration the available routes of administration and side effects. * Ensure that the antiemetics are given regularly, rather than on an as-needed basis. * Use one antiemetic first and go to maximal doses or intolerable side effects before switching or adding a second medication. * If the first agent is only partially effective at maximum doses, try a different class of antiemetic. * A combination of antiemetics may be necessary to help relieve that nausea and vomiting targeting different neurotransmitter pathways. ## Diagram of Antiemetic Therapy * **Stimulus:** Pain, repulsive sights and smells, emotional factors * **Input:** Sensory afferents and CNS pathways, H₁ receptor antagonists, muscarinic receptor antagonists * **Integration:** Higher centres, Dopamine antagonists, aprepitant, 5-HT₃ antagonists * **Output:** Nerves to somatic and visceral receptors * **Motion Sickness:** Labyrinth, Vestibular nuclei (H₁ and mACh receptors) * **Endogenous toxins, drugs:** Blood, Release of emetogenic agents (5-HT, prostanoids, free radicals), Visceral afferents (5-HT3 receptors), CTZ (NK1, D2 and 5-HT3 receptors) * **Stimuli from pharynx and stomach:** Nucleus of the solitary tract (mACh and H₁ receptors) ## Antiemetic Drugs * **5-HT₃ antagonists** * **Dopamine antagonists** * **Aprepitant (NK₁ antagonist)** * **Muscarinic receptor antagonists** * **H₁ receptor antagonists** * **Cannabinoids** * **Steroids** ## Antiemetic Drugs: Diagram **Note:** This diagram depicts the various drugs and their mechanism of action for treating nausea and vomiting. * **Ondansetron**, **granisetron**, **dolasetron**, **palonosetron:** Serotonin antagonist * **Metoclopramide**, **chlorpromazine**, **haloperidol**, **prochlorperazine:** Dopamine antagonist * **Octreotide**, **cinnarizine**: Miscellaneous * **Lorazepam:** Benzodiazepine * **Dronabinol:** Cannabinoids * **Scopolamine**, **glycopyrrolate:** Anticholinergic * **Dimenhydrinate**, **diphenhydramine**, **hydroxyzine**, **meclizine:** Antihistamine drugs * **Aprepitant:** Neurokinin antagonist * **Dexamethasone**, **methylprednisolone:** Steroids ## Diagram of the Process: * **Cancer chemotherapy drugs and dopamine agonists**: Cerebral cortex or CTZ (5-HT3, D2, and M1) * **Granisetron, ondansetron, metoclopramide, and phenothiazines**: Solitary tract nucleus (5-HT3, D2, M, H1, and NK1) * **All antiemetic drugs**: Vomiting Center (Medulla) * **Scopolamine and H1 antihistamines**: Vestibular apparatus * **Vagal afferent impulses**: Esophagus * **Granisetron and ondansetron**: Stomach (5-HT3, 5-HT1), Pylorus (5-HT1), Duodenum ## H1 Antagonists: Cinnarizine * **Indications:** Vertigo/Meniere's disease, nausea and vomiting, motion sickness, and vestibular symptoms of other origins. * **Mechanism of action:** Histamine H1 receptor antagonist, Voltage-dependent L-type calcium channel subunit alpha-1C, -1D, -1F & -1S antagonist, Voltage-dependent T-type calcium channel subunit alpha-1G, -1H & -11 antagonist, Dopamine receptor D1 & D2 binder, Muscarinic acethylcholine receptor binder ## Diagram of Cinnarizine: * **Effects by neurotransmitters:** * **CNS:** Blood-brain barrier * **Periphery:** * **Cerebellum:** (H, M) * **Inner ear (motion):** Aminoglycosides * **Sensory input (pain, smell, sight):** * **Effects by calcium channel blockers:** * **Blood-borne emetics:** Opioids, Cholinomimetics, Cardiac glycosides, L-DOPA, Bromocriptine, Apomorphine, Emetine (Ipecac) * **Stomach, Small Intestine (5HT):** * **Local Irritants:** Cytotoxic Drugs, CuSO4, Radiation, Bacteria, Viruses * **Solitary Tract Nucleus (5HT3, D2, M, H1, NK1, CB1):** * **Vagal and sympathetic afferents:** * **Glossopharyngeal and trigeminal afferents:** * **Pharynx (gagging):** ## H1 Receptor Antagonist: Dimenhydrinate * **Dimenhydrinate** is an antiemetics drug combination that contains diphenhydramine and theophylline. * **Indications:** Is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness. It is not effective in the treatment nausea associated with cancer chemotherapy. * **Mechanism of action:** Dimenhydrinate is a competitive antagonist at the histamine H1 receptor. * **Target:** Histamine H1 receptor antagonist ## Diagram of Dimenhydrinate * **CNS:** Blood-brain barrier * **Periphery:** - **Cerebellum: ** (H, M) * **Inner ear (motion):** Aminoglycosides * **Sensory input (pain, smell, sight):** * **Blood-borne emetics:** Opioids, Cholinomimetics, Cardiac glycosides, L-DOPA, Bromocriptine, Apomorphine, Emetine (Ipecac) * **Stomach, Small Intestine (5HT):** * **Local Irritants:** Cytotoxic Drugs, CuSO4, Radiation, Bacteria, Viruses * **Solitary Tract Nucleus (5HT3, D2, M, H1, NK1, CB1):** * **Vagal and sympathetic afferents:** * **Glossopharyngeal and trigeminal afferents:** * **Pharynx (gagging):** ## Cinnarizine and Dimenhydrinate * **Pharmacological effect:** Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (Non-sedating) generation agents. **Cinnarizine and Dimenhydrinate are:** * **Antihistamine and a calcium channel blocker.** Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. * **Metabolism:** Hepatic, CYP2D6 * **Adverse Effects:** Drowsiness/somnolence, fatigue, parkinsonism, headache, abdominal pain, nausea, and tremors * **Overdose:** Include delirium, hallucinations, and excitement. Patients may be violent and confused. ## Diagram of Cinnarizine: Multimodal Mechanism of Action * **Anti-vasoconstrictor activity:** Cinnarizine action on smooth muscle cells, Inhibits stimulated influx of Ca2+ into smooth muscle cell, Prevents vasoconstriction * **Decrease in Blood Viscosity:** Cinnarizine action on RBCs, Blocks Ca2+ entry into RBCs, Improves RBC flexibility, Reduces blood viscosity, Improves microcirculation * **Calming of Excited Vestibular Labyrinth:** Cinnarizine action on vestibular hair cell, Blocks voltage-gated Ca2+ channels, Prevents entry of Ca2+ into hair cells of contralesional side, Reduces release of neurotransmitters, Decreases firing frequency * **Cell Protective effect:** * **Improves Vestibular dysfunction:** ## Diagram: Cinnarizine and Dimenhydrinate: Dual Mechanism of Action * **Labyrinth:** Semicircular canal, Cochlear nerve, Utricle, Saccule, Cochlea, Membranous ampullae * **Vestibular nuclei:** Superior vestibular nucleus, Lateral vestibular nucleus, Interior vestibular nucleus, Medial vestibular nucleus * **Cinnarizine** * Calcium antagonist properties * Acts on labyrinth * Improves cerebral circulation * **Dimenhydrinate** * Anticholinergic and antihistaminic properties. * Centrally acting mechanism of action. * Anti-vertiginous: regulatory effect on vestibular nuclei. * Anti-emetic: affects related vegetative centers in the brainstem. ## Serotonin 5-HT3 Antagonists: Ondansetron * **Indications:** Orally and intravenously administered for the prevention of: * Nausea and vomiting associated with emetogenic cancer chemotherapy. * Postoperative nausea and vomiting. * **Mechanism of action:** Selective antagonist of the serotonin receptor subtype, 5-HT3. * **Target:** 5-HT3A antagonist, 5-HT4 agonist, Mu-type opioid receptor binding ## Diagram of Ondansetron * **CNS:** Blood-brain barrier * **Periphery:** * **Cerebellum:** (H, M) * **Inner ear (motion):** Aminoglycosides * **Sensory input (pain, smell, sight):** * **Blood-borne emetics:** Opioids, Cholinomimetics, Cardiac glycosides, L-DOPA, Bromocriptine, Apomorphine, Emetine (Ipecac) * **Stomach, Small Intestine (5HT):** * **Local Irritants:** Cytotoxic Drugs, CuSO4, Radiation, Bacteria, Viruses * **Solitary Tract Nucleus (5HT3, D2, M, H1, NK1, CB1):** * **Vagal and sympathetic afferents:** * **Glossopharyngeal and trigeminal afferents:** * **Pharynx (gagging):** ## Ondansetron: Adverse Effects * **Metabolism:** Hepatic, cytochrome P450 (CYP1A2, CYP2D6 and CYP3A4). Competes with other drugs for metabolism. * **Adverse Effects:** * **Prolongation of the QTc interval.** The use of ondansetron in pregnancy is not recommended. * **Overdoses:** "Sudden blindness" (amaurosis) of 2 to 3 minutes duration plus severe constipation. Hypotension (and faintness). Vasovagal episode with transient second-degree heart block. Neuromuscular abnormalities, autonomic instability, somnolence, and a brief generalized tonic-clonic seizure. * The most common side effects of 5-HT3 antagonists are headache, constipation, and diarrhea. * Dolasetron has been correlated to fatal torsade des pointes. ## Anticholinergic Drugs: Scopolamine * **Belladonna alkaloid** with anticholinergic effects. * **Mechanism of action:** As an acetylcholine analogue, scopolamine antagonizes muscarinic acetylcholine receptors (mAChRs) in the CNS and throughout the body, inducing alteration of the parasympathetic nervous system and cholinergic signaling. * **Target:** M1-M5 mAChRs inhibitor * **Adverse effects:** Xerostomia, Dizziness, Drowsiness, Agitation, Mydriasis, Hypotension. * **Medical indications:** Primarily used to prevent motion sickness. Used as well for the prevention of postoperative nausea and/or vomiting prevention. ## Neurokinin Antagonist: Aprepitant * **Indications:** Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy. * **Mechanism of actions:** Is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. * **Target:** Substance-P antagonist * **Metabolism:** Hepatic, CYP3A4. * **ADVERSE EFFECTS:** Asthenia/Fatigue, Anorexia, Constipation, Diarrhea, Nausea, and hiccups. ## Diagram of Aprepitant * **Nervous System:** * **CNS:** Blood-brain barrier * **Periphery:** * **Cerebellum:** (H, M) * **Inner ear (motion):** Aminoglycosides * **Sensory input (pain, smell, sight):** * **Chemoreceptor Trigger Zone (Area Postrema):** (5HT, D2, M, CB1) * **Blood-borne emetics:** Opioids, Cholinomimetics, Cardiac glycosides, L-DOPA, Bromocriptine, Apomorphine, Emetine (Ipecac) * **Stomach, Small Intestine (5HT):** * **Local Irritants:** Cytotoxic Drugs, CuSO4, Radiation, Bacteria, Viruses * **Solitary Tract Nucleus (5HT3, D2, M, H1, NK1, CB1):** * **Vagal and sympathetic afferents:** * **Glossopharyngeal and trigeminal afferents:** * **Pharynx (gagging):** ## Aprepitant * **Modulate the cytotoxic of chemotherapeutic agents in CNS** ## Diagram of Aprepitant's Mechanism of Action * **EGFR:** * **RAS:** * **GTP:** * **SOS:** * **Rho:** * **Rock:** * **PMLC:** * **Cell cortex contraction:** * **Cell migration:** * **SP:** * **NK-1 receptor:** * **T-K or c-Src:** * **IP3:** * **PLC:** * **PKB or Akt:** * **RAFI:** * **MEK:** * **MAPKS:** * **Adenylate cyclase:** * **PLA:** * **ATP:** * **CAMP:** * **PGS:** * **LXs:** * **TXA2:** * **PKA:** * **T-K:** * **DAG:** * **PKC:** * **ERK1/2:** * **Phosphorylation:** * **Antiapoptotic effect:** * **Cell proliferation:** # Cannabinoids: Dronabinol * **Dronabinol** (marketed as Marinol) is a synthetic form of delta-9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive component of cannabis (marijuana). * **Mechanism of action:** * Weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, which results in the well-known effects of smoking cannabis. * Inhibit endorphins in the emetic center, suppress prostaglandin synthesis, and/or inhibit medullary activity through an unspecified cortical action. * **Target:** Cannabinoid receptor 1 and 2 agonist. * **Metabolism:** Hepatic, Cytochrome P450. * **Adverse Effects:** Headache, Nausea, Appetite enhancement, Reduced pain, and changes in emotional and cognitive processes. * **Indications:** For the treatment of anorexia associated with weight loss in patients with AIDS, and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. **Cannabinoid hyperemesis syndrome:** A paradoxical and rare condition secondary to daily-long term users of marijuana or other cannabis products (including dronabinol). **Severe and repeated bouts of vomiting**: Dehydration, electrolyte disturbances, and even death. ## Diagram of Dronabinol * **Nervous System:** * **CNS:** Blood-brain barrier * **Periphery:** * **Cerebellum:** (H, M) * **Inner ear (motion):** Aminoglycosides * **Sensory input (pain, smell, sight):** * **Chemoreceptor Trigger Zone (Area Postrema):** (5HT, D2, M, CB1) * **Blood-borne emetics:** Opioids, Cholinomimetics, Cardiac glycosides, L-DOPA, Bromocriptine, Apomorphine, Emetine (Ipecac) * **Stomach, Small Intestine (5HT):** * **Local Irritants:** Cytotoxic Drugs, CuSO4, Radiation, Bacteria, Viruses * **Solitary Tract Nucleus (5HT3, D2, M, H1, NK1, CB1):** * **Vagal and sympathetic afferents:** * **Glossopharyngeal and trigeminal afferents:** * **Pharynx (gagging):** ## Dronabinol: Adverse Effects * **Metabolism:** Hepatic, Cytochrome P450 * **Adverse effects:** Headache, Nausea, Appetite enhancement, Reduced pain, and changes in emotional and cognitive processes. ## Chemotherapy Nausea Treatment * **Low risk of emesis:** * **Prechemotherapy:** Dexamethasone, Metoclopramide + diphenhydramine, Prochlorperazine + lorazepam * **Postchemotherapy (delayed emests):** None * **Moderate risk of emesis:** * **Prechemotherapy:** 5HT₃ antagonist + dexamethasone, 5HT₃ antagonist + dexamethasone + NK₁ antagonist * **Postchemotherapy (delayed enests):** Aprepitant (days 2 and 3), Dexamethasone or 5HT₃ antagonist (days 2-3 or 4), Aprepitant (days 2-3, if used prechemo) + dexamethasone (days 2-4) ± lorazepam (days 2-4) * **High risk of emesis:** * **Prechemotherapy:** 5HT₃ antagonist + dexamethasone + NK₁ antagonist + lorazepam, 5HT₃ antagonist/NK₁ antagonist + dexamethasone * **Postchemotherapy (delayed emests):** Dexamethasone + aprepitant, Dexamethasone (days 2-4) + aprepitant (days 2 and 3) ± lorazepam (days 2-4) ## Chemotherapy Nausea & Vomiting Treatment * **Ondansetron and dolasetron:** For the prevention and treatment of postoperative vomiting * **Ondansetron and granisetron:** To prevent nausea and vomiting caused by radiation therapy ## Treatment During Pregnancy * **H1 antagonists:** Are a safe option for the treatment of nausea and vomiting, and motion sickness in childbearing women. * **Doxylamine:** A first-generation antihistamine, with vitamin B6 (pyridoxine) was approved for the treatment of morning sickness in pregnant women. * **Meclizine:** For the treatment of vertigo, meclizine is the drug of choice in pregnancy. ## Nausea and Vomits (Pharmacological treatment) | **Family** | **Mechanism of action (molecular process)** | **Physiological effects** | **Pharmokinetics (ADME)** | **Indications** | **Adverse effects** | **Dosage** | |---|---|---|---|---|---|---| | H1R antagonist (cinnarizine, cyclizine, promethazine). | | | | | | | | Muscarinic antagonist (hyoscine) | | | | | | | | Dopamin receptors antagonist (fenotiacins, droperidol, haloperidol, metoclopramide, domperidone) | | | | | | | | Serotonin receptors antagonist (granisetron, ondansetron, palonosetron, tropisetron, dolasetron) | | | | | | | | Cannabinoids agonist (nabilon, dronabinol) | | | | | | | | Neurokinin antagonist (aprepitant, fosaprepitant) | | | | | | | | Glucocorticoids (dexametasone, metilprednisolone) | | | | | | | | Benzodiazepines (loracepam, aplrazolam) | | | | | | | ## 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