Antiemetic Antimuscarinics


Article Author:
Allan Migirov


Article Editor:
Albert Yusupov


Editors In Chief:
Sherri Murrell


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
11/6/2019 10:47:53 PM

Indications

Several medications indicated for antiemetic use produce antimuscarinic effects, most often as part of their adverse effect profiles. This article will focus on scopolamine, a medication that acts as an antiemetic primarily through its antimuscarinic mechanism of action.[1]

Two common indications for the use of scopolamine are for motion sickness and postoperative nausea and vomiting (PONV). Less common indications are also listed below.

  1. Motion Sickness
    • A scopolamine patch is indicated for the prophylaxis of motion sickness in patients with a prior history of the condition.
    • It can also be used to treat existing motion sickness if avoidance of stressor is not possible.
    • Although a transdermal patch is more common, a faster onset has been reported with the combination of transdermal scopolamine with oral scopolamine, discussed further in “Administration.”[2][3][4]
  2. Postoperative Nausea and Vomiting (PONV)
    • A scopolamine patch is indicated as part of a complete anesthetic plan, in conjunction with additional antiemetics, for patients with increased risk of PONV.
    • The following factors have been found to correlate with increased risk of PONV:
      1. Female gender 
      2. Non-smoker status 
      3. History of PONV
      4. History of motion sickness
      5. Young age
      6. History of migraine
      7. Obesity
      8. Use of postoperative opioids
      9. Use of inhalational agents including N2O
      10. A long duration of anesthesia 
    • The following factors may contribute to increased risk of PONV, but their significance is currently unclear[5]
      1. Type of surgery (e.g., open versus laparoscopic)
      2. Presence of postoperative pain
      3. Postoperative pain with a pelvic or visceral origin
    • One objective measure developed and commonly used is the simplified Apfel score, which comprises the following factors:
      1. Female gender 
      2. Non-smoker
      3. History of PONV
      4. Use of postoperative opioids
    • If three or four of the Apfel score conditions are present, scopolamine is an additional antiemetic medication that the clinician can add to the patient’s care plan. However, an Apfel score of 3 or 4 does not necessitate the use of scopolamine; likewise, a patient with an Apfel score of 2 or lower may still receive scopolamine.[6][5][7]
  3. Enhanced Recovery After Surgery (ERAS) Protocols
    • Many centers implement ERAS protocols for various types of surgeries. A crucial component of these protocols is the control of PONV. ERAS protocols vary from center-to-center and on the type of surgery. Although some studies don’t explicitly report the sequence/types of antiemetics used, several studies reported the use of scopolamine as a standard part of their ERAS protocol.[8][9][10]
  4. Refractory nausea and vomiting
  5. Dizziness
  6. Vertigo
  7. Drooling[2]
  8. Depression (off-label)[11][12][13]

Mechanism of Action

Acetylcholine Receptors The nervous system utilizes several neurotransmitters for communication and function. The primary neurotransmitter of the parasympathetic nervous system is acetylcholine (ACh). ACh is synthesized in the cytoplasm of presynaptic neurons by the enzyme choline acetyltransferase (ChAT). It is subsequently relocated to synaptic vesicles by vesicular acetylcholine transporter (VAChT), where it is stored. When the presynaptic neuron becomes stimulated via depolarization, ACh gets released through exocytosis into the synaptic cleft, where it acts on postsynaptic receptors by binding to them. These receptors include muscarinic and nicotinic types, each with their respective subtypes. There are five subtypes of muscarinic receptors, M1 to M5, all of which are G protein-coupled receptors.[14]

ScopolamineScopolamine (also known as hyoscine) is an alkaloid compound. It competitively the action of ACh at muscarinic receptors both centrally and peripherally. It is strongly selective to muscarinic receptors but is non-selective between the muscarinic receptor subtypes (M1 to M5). Because ACh is the principal neurotransmitter of the parasympathetic nervous system, scopolamine acts as a parasympatholytic agent.[1][13][15]

Nausea and VomitingMultiple proposed mechanisms of nausea and vomiting involve various systems (e.g., vestibular, gastrointestinal, etc.). Furthermore, the specific pathways that these systems utilize to stimulate nausea and vomiting are ambiguous and still debated. The precise locations and functions of nervous system structures involved in nausea and vomiting are also not fully understood.

For these reasons, the exact mechanisms by which scopolamine prevents nausea and vomiting are unclear. The proposed pathways generally involve scopolamine inhibiting cholinergic communications between higher CNS centers, the reticular formation in the brainstem, the vestibular nuclei, the cerebellum, the glossopharyngeal nerve, and the vagus nerve. Additional structures may be involved, and scopolamine’s exact role is unclear. Furthermore, all five muscarinic receptor subtypes M1 to M5 show expression in the brain, and the roles of each subtype relative to nausea and vomiting remain unclear.[15][16][17][18]

A discussion of the mechanisms involved in scopolamine’s adverse effects is in “Adverse Effects.”

Administration

Note: Although the following methods of administration appear in the published literature, every patient should receive a plan specific to them based on their medical team’s assessment and expertise. Prior to the administration of scopolamine, a thorough history, and physical exam are necessary to rule out contraindications and to anticipate adverse effects accurately. See “Contraindications” and “Adverse Effects” for more detail.

Transdermal vs. Oral

The preferred method for the administration of scopolamine is via a transdermal therapeutic system (TTS-patch) due to increased bioavailability and decreased adverse effects. There is a 1.5 mg patch commercially available and is generally the specific patch used. As previously mentioned, oral scopolamine has been shown to be effective when combined with the transdermal patch. However, this mode of administration is uncommon.

Placement Location and Timing

The 1.5 mg patch should be placed behind the patient’s ear on an area of skin without hair. Placement should occur several hours before the patient’s surgery. Reports range from 4 hours before the anticipated end of the procedure to the night before surgery. If used for the prophylaxis of motion sickness, placement should occur 6 to 8 hours before the nausea-inducing event. Due to the timing requirement, patients presenting for surgery should be evaluated for PONV risk as early as possible to properly formulate an anesthetic plan with enough time to permit the ideal usage of scopolamine if indicated.

The patch is designed to release an initial priming dose to achieve steady-state concentrations in an acceptable amount of time. It then continues to release medication slowly, a topic discussed in greater detail in “Mechanism of Action.” Due to its mechanism of release, if the continual antiemetic effect is required, the patch can be replaced every 72 hours. If scopolamine is used preoperatively for the prophylaxis of PONV, the patch can be removed the day following surgery.

Importance of Hand Hygiene

A crucial element of the administration of scopolamine is the counseling of the patient and/or their family. In addition to remaining vigilant about adverse effects, anyone who will be removing the patch needs to understand the importance of hand hygiene. After removal of the scopolamine patch, the skin location where the patch was, and the operator’s hands, require thorough washing with soap and water. Patients should also be instructed to avoid touching their faces, especially their eyes, after touching a scopolamine patch. A significant number of adverse effects related to the scopolamine patch are due to contamination by the patient or by an individual changing or touching the patch.[2][3][5][15][16]

Adverse Effects

Scopolamine’s adverse effect profile is due to its antagonism of muscarinic receptors. The more commonly-reported adverse effects are listed below, with xerostomia and CNS symptoms being significantly more common than ophthalmic symptoms. However, scopolamine non-selectively affects all five muscarinic receptor subtypes (M1 to M5), and anticholinergic symptoms, or anticholinergic syndrome, are theoretically possible.[10] Additionally, there are over 600 medicinal products with anticholinergic activity. The antimuscarinic effects of these products have the potential to exacerbate the adverse effects of scopolamine.[1][19][20]

Most Common

  • Xerostomia (dry mouth)
  • Central Nervous System Symptoms:
    • Dizziness
    • Confusion
    • Agitation
    • Delirium
  • Ophthalmic Symptoms:
    • Visual impairment including blurred vision
    • Mydriasis

The following rare adverse effects have also been observed[10][21][22][23][24][25]:

  • Acute angle-closure glaucoma
  • Urinary retention
  • Withdrawal symptoms upon cessation of scopolamine

Discussion on Ophthalmic Symptoms and GlaucomaMydriasis is a potential complication of scopolamine. Although reports exist of bilateral cases, the literature suggests that the majority of cases of mydriasis are unilateral and ipsilateral to the side of their scopolamine patch, caused by the patient self-contaminating by touching their patch and then touching their eyes.[2]

There are case reports of acute angle-closure glaucoma after the administration of scopolamine. This complication is rare. Patients affected by this complication likely have underlying pathology or abnormal anatomy that predisposes them to acute angle closure in the event of mydriasis through at least two mechanisms. Aqueous humor becomes blocked from flowing from the posterior to the anterior chamber of the eye, building up intraocular pressure. Patients can present with the following signs and symptoms:

  • Nausea and vomiting
  • Severe headache
  • Severe ocular pain
  • Blurred vision
  • Red-eye
  • Dilation of pupil

Glaucoma is an ophthalmic emergency that can result in blindness if untreated promptly, and an ophthalmology consultation is important.[26][27][28][29]A distinction should be made with patients with open-angle glaucoma as these patients can safely use transdermal scopolamine patches.[30]

Elderly PatientsElderly patients are at an increased risk of and are more vulnerable to adverse anticholinergic effects due to differences in metabolism and excretion of medications. In the elderly, antimuscarinic medications may correlate with increased morbidity, for several reasons, including due to increased risk of falls. Scopolamine and antimuscarinic medications should be used cautiously in elderly patients.[31][32][33][34][35]

Contraindications

The following are contraindications to scopolamine:

  • Hypersensitivity to the medication or a component of the delivery system
  • Glaucoma
  • Urinary retention
  • Pregnancy

Although one study mentions pregnancy as a contraindication for scopolamine in one study, another study indicates that although the scopolamine crosses the placenta, it’s considered nonteratogenic.[4][15]

Toxicity

The reversal of scopolamine toxicity is not a widely reported topic. However, based on the mechanism of toxicity, physostigmine can be used to reverse anticholinergic symptoms. There are reports of the use of physostigmine in cases of scopolamine toxicity. The patient then requires monitoring for a cholinergic crisis with atropine available at the bedside. Additionally, as with most poisonings, vital signs and ECG should be obtained and monitored.[10][36][37]

Enhancing Healthcare Team Outcomes

Postoperative nausea and vomiting (PONV) is a ubiquitous complaint when caring for postoperative patients. The incidence is estimated to be about 30% in the average patient and can rise as high as 70% in the high-risk patient. PONV is a significant concern because it prolongs recovery room time, can lead to increased hospital admissions, and can lead to unanticipated complications. Additionally, the prevention of PONV is vital to patients.

A patient’s risk of experiencing PONV can be reliably anticipated and predicted using several measures, including the Apfel score. In patients with increased risk, a multimodal approach, including the use of multiple antiemetic medications, in the prevention of PONV, is the proper approach.[5] [Level I] One potential antiemetic medication that has shown effectiveness in reducing the incidence of PONV is the transdermal scopolamine patch.[38] [Level I]

Due to the pharmacokinetics and pharmacodynamics of the scopolamine patch, it requires application several hours before the start of the patient’s surgery. It can also be applied the previous night. The patient’s healthcare team must remain vigilant about identifying patients who are at high risk for PONV so that if scopolamine is indicated, there is sufficient time before the procedure to administer the drug effectively.

Scopolamine commonly causes dry mouth, blurred vision, and sedation. As an antimuscarinic medication, scopolamine has the potential to cause anticholinergic symptoms, including tachycardia, urinary retention, and acute angle-closure glaucoma. There are also reports of withdrawal symptoms from the medication. The patient’s health care team must be aware of these potential complications to recognize them and begin management as soon as possible; this is especially true for elderly patients who are at increased risk of complications, including falls.[10][21][29][38] [Level II]

A collaborative healthcare team approach is the best method for addressing PONV. Clinicians need to accurately identify which patients will be candidates for anti-emetic prophylaxis or therapy and coordinate with nursing and pharmacy for its delivery. Nursing will be administering the medication and needs to fully understand the points discussed in this activity regarding proper administration and handling of the drug, particularly in patch form. The pharmacist needs to complete a full drug-drug interaction check and verify dosing, while also watching for mitigating factors like age, that may require therapy modification. Both the pharmacist and nurse must report any issues or concerns to the treating clinician. These points highlight some of how an interprofessional team approach will be most successful in providing PONV care. [Level V]

Finally, a common mechanism of ophthalmic symptoms from scopolamine is self-contamination by the patient. The health care team, including the pharmacist, must counsel the patient on hand washing and proper hand hygiene after touching the scopolamine patch. In addition to the morbidity associated with the actual adverse effect, the clinical signs associated with unilateral mydriasis may often be misinterpreted, leading to misdiagnosis, increased costs, and delay of proper treatment.[2] [Level V]


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Antiemetic Antimuscarinics - Questions

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A 64-year-old male presents to his provider for a health maintenance visit. The patient has a history of diabetes mellitus controlled with lifestyle modification, hyperlipidemia controlled with a statin, cataracts actively managed by an ophthalmologist, benign prostatic hyperplasia, with occasional symptoms of urinary retention, actively managed by a urologist, and severe motion sickness when in a car. Additionally, the patient reports occasional insomnia for which he self-medicates with diphenhydramine. Due to its potential side-effect profile, which of the following components of the patient’s medical history are a contraindication to the use of diphenhydramine?



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A 72-year-old female is admitted for a hip fracture after a fall. The decision is made to perform total hip arthroplasty. The patient reports a history of severe postoperative nausea and vomiting in the past. She is administered an antiemetic medication in the form of a patch in the pre-surgery area. While waiting for her procedure, the patient reports a sudden-onset headache, nausea, blurry vision, and a halo when she looks at lights. A history of which of the following conditions would have most likely predisposed the patient to this adverse effect?



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A 38-year-old female is discharged after an elective surgical procedure at an outpatient center. A full history and physical exam are performed, and no contraindications to a transdermal scopolamine patch are discovered. The patch is applied behind her right ear, and she is directed to remove it at home after her procedure. Which of the following additional instructions should the patient be given to safely facilitate removal of the patch?



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A 22-year-old male with no previous medical history complains of dry mouth after using an antiemetic medication that is applied via a transdermal patch. Which of the following mechanisms is most likely responsible for his complaint?



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A 67-year-old man presents to his primary care provider to inquire about medication for sea-sickness for his upcoming vacation. The clinician prescribes a medication that can be applied behind the patient's ear in the form of a patch. Based on the mechanism of action of the drug, which of the following should be included in the list of adverse effects that the patient is counseled about?



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A 68-year-old woman with a history of severe motion sickness presents to her primary care provider to obtain anti-nausea medication one week before her trip on a 14-day cruise ship. The provider prescribes a transdermal patch to place behind her ear, explains proper usage, and counsels her on medication safety. When should the patch be applied, and how often does it need to be changed?



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A 66-year-old woman scheduled for surgery was placed on the hospital’s Enhanced Recovery After Surgery (ERAS) protocol which included multiple antiemetic medications. The surgery was completed without complication. However, in the recovery room, the patient develops delayed emergence. Additionally, she demonstrates signs of delirium, tachycardia, and mydriasis. An area of skin breakdown is noted next to a transdermal patch in her postauricular area. The patch is removed, and an antidote medication is administered. The patient’s mental status and symptoms return to baseline. Which of the following is the most likely complication of the antidote immediately prior to her return to baseline?



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A 38-year-old woman presents to the ambulatory surgery center for an elective orthopedic procedure. She has a history of asthma that is well-controlled since childhood and prediabetes that is being managed with lifestyle modification. 10 years ago, the patient received an appendectomy for acute appendicitis. She reports severe nausea and vomiting following the procedure. The patient does not take any medication except for a daily multivitamin. She consumes alcohol socially and denies the use of tobacco or drugs. Prior to her current orthopedic procedure, the patient and her medical team agree on the use of an additional antiemetic prescription. The medication is applied as a transdermal patch behind her ear, several hours prior to her procedure. The patient is instructed to remove the transdermal patch the day following her surgery. She is also counseled on the potential risks of the medication as well as the importance of proper hand-hygiene following the handling of the patch. Which of the following is the most common side effect seen after use of this medication?



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Antiemetic Antimuscarinics - References

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