Antiemetics

Antiemetics are medications used to treat and/or prevent nausea and vomiting. These drugs act on different target receptors. The main classes include benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines, corticosteroids, atypical antipsychotics, cannabinoids Cannabinoids Cannabinoids are a class of compounds interacting with cannabinoid receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Cannabinoids, and antagonists of the following receptors: serotonin, dopamine, and muscarinic and neurokinin receptors. Anticholinergics and antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines are useful in the treatment of vestibular causes of nausea. Serotonin and neurokinin antagonists are effective in the management of chemotherapy-induced nausea and vomiting. Antiemetics should be used with caution, though, because of their adverse effects. Serotonin antagonists and some dopamine antagonists cause QT-interval prolongation. Dopamine antagonists are associated with extrapyramidal symptoms. Additionally, many agents cause sedation and have anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs effects, which can aggravate underlying diseases.

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Overview

Definition

Antiemetics are medications used to treat nausea and vomiting.

Classification

The following classes of drugs are used either alone or in combination for the prevention and treatment of nausea and vomiting:

  • Serotonin-receptor antagonists
  • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
  • Anticholinergics
  • Neurokinin-receptor antagonists
  • Dopamine-receptor antagonists
  • Cannabinoids
  • Antihistamines
  • Atypical antipsychotics
  • Benzodiazepines

General indications

  • Chemotherapy-induced nausea and vomiting:
    • Acute phase (within 24 hours)
    • Delayed phase (days 2–5)
  • Radiation-induced nausea and vomiting
  • Postoperative nausea and vomiting
  • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache-related nausea and vomiting
  • Opioid-induced nausea and vomiting
  • Gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis
  • Gastroparesis
  • Vestibular causes of nausea and vomiting
  • Hyperemesis gravidarum 

Physiology

Nausea and vomiting

  • Nausea: vague, unpleasant sensation of sickness or queasiness, associated with decreased gastric motility and, often, reverse small bowel peristalsis
  • Vomiting: forceful expulsion of stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach (and, often, small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine) contents

Control of nausea and vomiting

  • The vomiting center (area postrema), located in the medulla, is composed of different neuronal areas.
  • The vomiting center receives afferent input from the following sources:
    • The chemoreceptor trigger zone (CTZ):
      • In the area postrema of the medulla (4th ventricle), outside the blood–brain barrier (allowing detection of emetogenic stimuli)
      • Opioid, serotonin (5-hydroxytryptamine (5-HT3)), neurokinin 1 (NK1), and dopamine D2 receptors are present.
      • Stimulated by drugs (e.g., chemotherapeutic agents), hypoxia, toxins, acidosis, and radiation therapy
    • Afferent vagal fibers from the GI tract
      • Express serotonin 5-HT3 receptors
      • Stimulated by biliary or GI distention, infections, or irritation of the peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum or mucosa
    • Vestibular apparatus: rich in histamine H1 and muscarinic cholinergic (M1) receptors
    • Higher CNS centers (amygdala):
      • Particular sights, smells, or emotional stimuli (e.g., memory, dread, fear) may induce vomiting. 
      • Cerebral trauma can also lead to vomiting.

Specific causes

  • Gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache-related
  • Vestibular disorders
  • Disease-related (e.g., uremia, ileus)
  • Treatment-related (e.g., chemotherapy, opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, radiation)
  • Biochemical (e.g., elevated calcium)
  • Toxin-related (e.g., anorexia-cachexia syndrome)

Serotonin-Receptor Antagonists

Agents

  • Ondansetron
  • Dolasetron
  • Palonosetron
  • Granisetron

Mechanism of action

  • 5-HT3–receptor antagonist
  • Block serotonin receptors peripherally on intestinal vagal and spinal afferent nerves
  • Block serotonin receptors centrally in the area postrema and vomiting center

2nd-generation serotonin-receptor antagonist, palonosetron, has greater receptor affinity.

Pharmacokinetics

  • Administration:
    • Oral or IV routes
    • Ondansetron can be given IM.
    • Granisetron is available in transdermal form.
  • Extensively metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver by:
    • CYP1A2
    • CYP2D6
    • CYP3A4
  • Ondansetron, the prototypical drug type, has a half-life of 3–6 hours.
  • Palonosetron, metabolized mainly by CYP2D6, has a longer half-life (40 hours) than the other agents.
  • Excretion: mostly renal

Indications

  • Chemotherapy-induced nausea and vomiting
  • Radiation-induced nausea and vomiting
  • Postoperative nausea and vomiting

Adverse effects

  • Headache
  • Fatigue
  • Malaise
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Increase in serum aminotransferases
  • QT-interval prolongation
  • Serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome

Contraindications

  • Hypersensitivity to the drug
  • Prolonged QT interval
  • Severe hepatic impairment
  • Caution against concurrent use with selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (potential increase in 5-HT3)

Glucocorticoids

Agents

  • Dexamethasone
  • Methylprednisolone

Mechanism of action

  • Exact mechanism unknown
  • Inhibit prostaglandin synthesis and decrease peritumoral inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Interact with glucocorticoid receptors in the nucleus tractus solitarius and area postrema
  • Increase sensitivity of 5-HT3 receptors when combined with 5-HT3–receptor blockers

Pharmacokinetics

  • Absorption depends on the route of administration
  • Extensively metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
  • Excretion: renal

Indications

  • Chemotherapy-induced nausea and vomiting
  • Radiation-induced nausea and vomiting
  • Postoperative nausea and vomiting

Adverse effects

Multisystemic effects include (but are not limited to):

  • Cardiovascular: hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Dermatologic: striae
  • Endocrine: diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
  • GI: dyspepsia, ulcers
  • Immunosuppression
  • Musculoskeletal: osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis, increased risk of fractures, osteonecrosis, myopathy
  • Neuropsychiatric: psychosis, agitation, insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Ophthalmic: glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma, cataract

Contraindications

  • Hypersensitivity to the components of the medication
  • Concurrent administration of the live vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination or live attenuated vaccines
  • Uncontrolled diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • Uncontrolled hypertension Uncontrolled hypertension Although hypertension is defined as a blood pressure of > 130/80 mm Hg, individuals can present with comorbidities of severe asymptomatic or "uncontrolled" hypertension (≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic) that carries with it a significant risk of morbidity and mortality. Uncontrolled Hypertension
  • Uncontrolled infections (viral, bacterial, fungal)
  • Glaucoma
  • Osteoporosis
  • Herpes simplex keratitis

Anticholinergics

Agent

Scopolamine (hyoscine)

Mechanism of action

Anticholinergics inhibit G-protein–coupled muscarinic receptors in the area postrema and vestibular nuclei.

Pharmacokinetics

  • Transdermal patch
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver 
  • Half-life: 9.5 hours
  • Excretion: renal

Indications

  • Motion sickness, nausea and vomiting due to vestibular diseases
  • Prevention of postoperative nausea and vomiting

Adverse effects

  • Dry mouth
  • Blurred vision
  • Bradycardia
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin flushing
  • Mydriasis
  • Urinary retention

Contraindications

  • Hypersensitivity to the drug
  • Allergy to belladonna alkaloids
  • Acute angle-closure glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma

Neurokinin-Receptor Antagonists

Agents

  • Aprepitant
  • Rolapitant
  • Fosaprepitant
  • Netupitant (in combination with palonosetron)

Mechanism of action

  • NK1 receptor (receptor for substance P) antagonist 
  • Inhibits NK1 receptors in the area postrema, nucleus tractus solitarius, and visceral afferent nerves

Pharmacokinetics

  • Given orally, IV
  • Fosaprepitant (parenteral) is converted to aprepitant.
  • Half-life:
    • Aprepitant: approximately 9–13 hours
    • Rolapitant: 7 days
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver via CYP3A4
  • Excreted in urine and feces

Indications

Indications include chemotherapy-induced nausea and vomiting (effective for delayed emesis).

Adverse effects

  • Hypersensitivity reactions
  • Headache, dizziness
  • Drowsiness
  • Elevation of serum aminotransferases
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Aprepitant: inhibition of CYP3A4 enzyme
  • Rolapitant: inhibition of CYP2D6 enzyme

Contraindications

  • Hypersensitivity to the drug
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Severe hepatic impairment
  • Aprepitant interacts with substrates of the CYP3A4 enzyme (risk differs depending on the drug): 
    • Concurrent intake contraindicated with pimozide, astemizole, cisapride, ivabradine
    • Caution with warfarin, corticosteroids, and benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
  • Rolapitant: concurrent intake with CYP2D6 substrates with narrow therapeutic index (e.g., thioridazine, pimozide)

Dopamine-Receptor Antagonists

Agents

  • Prochlorperazine
  • Metoclopramide
  • Domperidone (investigational drug protocol only)

Mechanism of action

Generally, all agents act via D2-receptor antagonism, decreasing release of excitatory neurotransmitters, with some unique properties.

  • Prochlorperazine:
    • D2-receptor antagonist in the area postrema/CTZ
    • Also blocks muscarinic and histamine receptors
  • Metoclopramide:
    • An antagonist of D2 and 5-HT3 receptors in the area postrema
    • Increases response of GI tract to acetylcholine:
      • Increase in gastric peristalsis
      • Increase in lower esophageal sphincter tone
  • Domperidone:
    • An antagonist of peripheral D2 receptors in the GI tract → prokinetic effect:
      • Increase in gastric peristalsis
      • Increase in lower esophageal sphincter tone
    • Does not easily cross blood–brain barrier

Pharmacokinetics

  • Prochlorperazine:
    • Oral, IM, rectal
    • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver to N-desmethyl prochlorperazine
    • Excreted in feces
  • Metoclopramide:
    • Rapidly absorbed orally
    • Crosses blood–brain barrier, placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity
    • Undergoes conjugation in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Excreted in urine
  • Domperidone:
    • Absorbed orally
    • Hepatic metabolism
    • Excreted in feces and urine

Indications, adverse effects, and contraindications

Table: Indications, adverse effects, and contraindications of dopamine receptor antagonists
Prochlorperazine Metoclopramide Domperidone
Indications N/V caused by different conditions (e.g., chemotherapy-induced, postoperative, migraine)
  • N/V caused by different conditions
  • Refractory GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease
  • Diabetic gastroparesis
Requires FDA approval:
  • N/V associated with use of antiparkinson agents (dopamine agonists)
  • Severe GI motility disorders
Adverse effects
  • EPS
  • Arrhythmias (e.g., QT prolongation)
  • ↑ Prolactin
  • Galactorrhea
  • Anticholinergic effects (e.g., dry mouth, blurred vision)
  • Dizziness, drowsiness
  • NMS
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Leukopenia
  • ↑ Risk of death in dementia-related psychosis
  • EPS
  • Arrhythmias (e.g., QT prolongation)
  • ↑ Prolactin
  • Galactorrhea
  • Dizziness, drowsiness, seizure
  • Change in bowel habits
  • EPS rare (minimally crosses BBB)
  • Arrhythmias (e.g., QT prolongation)
  • ↑ Prolactin
  • Galactorrhea
Contraindications
  • Hypersensitivity to the drug
  • Use with drugs that increase EPS or prolong QT
  • Severe cardiovascular disorders including conduction abnormalities
  • Use with high dose hypnotics
  • Severe depression
  • Blood dyscrasias
  • Angle-closure glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
  • BPH
  • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
  • GI obstruction, perforation, hemorrhage
  • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
  • Seizure disorder
  • GI obstruction, perforation, hemorrhage
  • Use with CYP3A4 inhibitors
BBB: blood-brain barrier
BPH: benign prostatic hyperplasia Benign prostatic hyperplasia Benign prostatic hyperplasia (BPH) is a condition indicating an increase in the number of stromal and epithelial cells within the prostate gland (transition zone). Benign prostatic hyperplasia is common in men > 50 years of age and may greatly affect their quality of life. Benign Prostatic Hyperplasia
EPS: extrapyramidal symptoms (which include akathisia, tardive dyskinesia)
N/V: nausea and vomiting
NMS: neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome

Cannabinoids

Agents

  • Dronabinol
  • Nabilone (not available in the United States)

Mechanism of action

  • Agonist of cannabinoid receptor types B1 and B2 (CB1 and CB2) 
  • Effects come from activated CB1 in the CNS modulating release of neurotransmitters

Pharmacokinetics

  • Oral, > 90% absorption
  • Hepatic metabolism
  • Excretion: mostly via feces

Indications

  • Refractory chemotherapy-induced nausea and vomiting
  • Anorexia associated with AIDS

Adverse effects

  • Dizziness, somnolence, paranoia, euphoria
  • Exacerbation of depression, mania, schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, tachycardia
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Hyperemesis syndrome (associated with chronic cannabis use)

Contraindications

  • Hypersensitivity to the drug or components
  • Use with disulfiram- or metronidazole-containing products (within 2 weeks of intake)
  • Caution in those with history of substance abuse

Antihistamines

Agents

  • Cyclizine
  • Diphenhydramine
  • Doxylamine
  • Meclizine
  • Promethazine

Mechanism of action

  • H1-receptor antagonist
  • Inhibit H1 receptors in the area postrema and vestibular nucleus
  • 1st-generation antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines:
    •  Block muscarinic receptors in the vestibular nucleus and chemoreceptor trigger zone 
    • Cross the blood–brain barrier, causing sedation
  • Promethazine also inhibits D2 receptors.

Pharmacokinetics

  • Rapid absorption 
  • Widely distributed throughout the body
  • Hepatic metabolism

Indications

  • Nausea and vomiting due to vestibular dysfunction
  • Postoperative nausea and vomiting
  • Combination doxylamine–pyridoxine for hyperemesis gravidarum

Side effects

  • Antihistamine effects: sedation
  • Antimuscarinic effects:
    • Dry mouth
    • Blurred vision
    • Tachycardia
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin flushing
    • Mydriasis
    • Urinary retention
    • Decreased bowel sounds

Contraindications

  • Hypersensitivity to the medication
  • Avoid use of sedating agents with other medications that cause drowsiness.

Atypical Antipsychotics

Agent

Olanzapine

Mechanism of action

  • Dopamine (D1–D4) and 5-HT3–receptor antagonist
  • Also an antagonist of antimuscarinic and H1 receptors

Pharmacokinetics

  • Absorption depends on the route of administration (oral, IM, IV)
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver by conjugation and oxidation
  • Excreted in feces and urine

Indications

Indications include chemotherapy-induced nausea and vomiting (acute and delayed).

Adverse effects

  • Anticholinergic effects (e.g., xerostomia, urinary retention)
  • Dyslipidemia
  • Extrapyramidal symptoms (e.g., akathisia, tardive dyskinesia, dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia)
  • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia due to dopamine-receptor blockade
  • Hyperglycemia
  • Hypersensitivity reactions
  • Increased appetite, weight gain
  • Leukopenia, neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
  • Neuroleptic malignant syndrome
  • Sexual dysfunction
  • Suicidal ideation
  • QT prolongation

Contraindications

  • Hypersensitivity to the drug and components
  • Use with caution in those with:
    • Dementia-related psychosis (increased risk of death)
    • Parkinson disease
    • GI motility (exacerbates condition)
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures (increased risk of seizures)
    • Urinary retention

Benzodiazepines

Agent

Lorazepam

Mechanism of action

  • GABA receptor agonist (inhibition of neuronal excitability)
  • Possible depression of the area postrema

Pharmacokinetics

  • IV, IM, oral
  • Rapidly and readily absorbed
  • Hepatic metabolism (glucuronic acid conjugation)
  • Excreted mainly in the urine

Indications

  • Chemotherapy-induced nausea and vomiting
  • Postoperative nausea and vomiting

Adverse effects

  • Anterograde amnesia
  • Confusion
  • Sedation, dizziness (hazardous with activities, e.g., driving)
  • Respiratory depression
  • Ataxia
  • Propylene glycol toxicity (solvent used in parenteral lorazepam)
  • Paradoxical (disinhibitory) reactions (e.g., hyperactivity, aggressive behavior)
  • Withdrawal syndrome (with rapid discontinuation)

Contraindications

  • Hypersensitivity to the drug
  • Acute narrow-angle glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma 
  • Parenteral form:
    • Hypersensitivity to propylene glycol, polyethylene glycol, benzyl alcohol
    • Intraarterial administration
    • Sleep apnea
    • Respiratory impairment 
  • Avoid administration with other CNS depressants, including opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics.
  • Avoid in individuals with a history of substance abuse.

Comparison of Antiemetics

Table: Comparison of indications for antiemetics
Drug class Representative drug Indications
Serotonin receptor antagonists Ondansetron
    N/V associated with:
  • Chemotherapy
  • Radiation
  • Postoperative state
Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids Dexamethasone
Anticholinergics Scopolamine
  • Prevention of postoperative N/V
  • Vestibular diseases
Neurokinin-receptor antagonists Aprepitant Chemotherapy-induced N/V (effective for delayed emesis)
Dopamine-receptor antagonists Prochlorperazine
    N/V from various causes:
  • Chemotherapy
  • Radiation
  • Postoperative state
  • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache
  • Opioids
  • Gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis
  • Vestibular diseases
Cannabinoids Dronabinol
  • Refractory N/V from chemotherapy
  • Anorexia associated with AIDS
Antihistamines Doxylamine
    N/V from:
  • Vestibular diseases
  • Postoperative state
  • Hyperemesis gravidarum
Atypical antipsychotics Olanzapine Chemotherapy-induced N/V
Benzodiazepines Lorazepam
    N/V associated with:
  • Chemotherapy
  • Postoperative state
N/V: nausea and vomiting

References

  1. Athavale, A., Athavale, T., Roberts, D. M. (2020). Antiemetic drugs: what to prescribe and when. Australian Prescriber 43(2):49–56. https://doi.org/10.18773/austprescr.2020.011
  2. Darmani, N. A. (2010). Mechanisms of broad-spectrum antiemetic efficacy of cannabinoids Cannabinoids Cannabinoids are a class of compounds interacting with cannabinoid receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Cannabinoids against chemotherapy-induced acute and delayed vomiting. Pharmaceuticals 3:2930–2955. https://doi.org/10.3390/ph3092930
  3. Dexamethasone. Medscape. Retrieved June 16, 2021, from https://reference.medscape.com/drug/decadron-dexamethasone-intensol-dexamethasone-342741#10
  4. Din, L., Preuss, C. (2021). Prochlorperazine. StatPearls. Retrieved June 17, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK537083/
  5. Ghiasi, N., Bhansali, R., Marwaha, R. (2021). Lorazepam. StatPearls. Retrieved June 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK532890/
  6. Hodgens, A., Sharman, T. (2021). Corticosteroids. StatPearls. Retrieved June 16, 2021 Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK554612/
  7. Ibrahim, M., Preuss, C. (2021). Antiemetic Neurokinin-1 Receptor Blockers. StatPearls. Retrieved June 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK470394/
  8. Isola, S., Hussain, A., Dua, A., Singh, K., Adams, N. (2021). Metoclopramide. StatPearls. Retrieved on June 17, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK519517/
  9. Jennings, L., Krywko, D. (2021). Hyperemesis gravidarum. StatPearls. Retrieved June 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK532917/
  10. McQuaid, K. R. (2017). Drugs used in the treatment of gastrointestinal diseases. In Katzung, B. G., et al. (Eds.), Basic & Clinical Pharmacology. New York: McGraw-Hill Medical, pp. 282, 1097–1098, 1103–1106.
  11. Methylprednisolone. Medscape. Retrieved June 16, 2021, from https://reference.medscape.com/drug/medrol-medrol-dosepak-methylprednisolone-342746#10
  12. Prochlorperazine. Medscape. Retrieved June 17, 2021, from https://reference.medscape.com/drug/compazine-spansules-prochlorperazine-342055#10
  13. Saudemont, G., Prod’Homme, C., Da Silva, A., Villet, S., Reich, M., Penel, N., Gamblin, V. (2020). The use of olanzapine as an antiemetic in palliative medicine: a systematic review of the literature. BMC Palliative Care 19(1):56. https://doi.org/10.1186/s12904-020-00559-4
  14. Schaefer, T., Zito, P. (2021). Antiemetic histamine H1 receptor blockers. StatPearls. Retrieved June 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK533003/
  15. Scopolamine. Medscape. Retrieved June 16, 2021, from https://reference.medscape.com/drug/transderm-scop-scopace-scopolamine-342057#10
  16. Sharkey, K.A., MacNaughton, W.K. (2017). Gastrointestinal motility and water flux, emesis, and biliary and pancreatic disease. Chapter 50 of Brunton L.L., Hilal-Dandan R., Knollmann B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172483503
  17. Theriot, J., Wermuth, H., Ashurst, J. (2020). Antiemetic serotonin-5-HT3 receptor blockers. StatPearls. Retrieved June 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK513318/

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