Antiemetic Antimuscarinics

Mechanism of Action

Acetylcholine Receptors

The nervous system utilizes many 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) and is subsequently relocated to synaptic vesicles by vesicular acetylcholine transporter (VAChT), where it is stored. When the presynaptic neuron becomes stimulated via depolarization, ACh is released through exocytosis into the synaptic cleft, which acts on presynaptic and postsynaptic receptors by binding to them. These receptors include muscarinic (M) and nicotinic (N) types, each with their respective subtypes. There are 5 subtypes of muscarinic receptors, M1 through M5, all of which are G protein-coupled.[14]

The Role of Scopolamine in Nausea and Vomiting 

Scopolamine (also known as hyoscine) is an alkaloid compound. Scopolamine competitively antagonizes the action of ACh at muscarinic receptors both centrally and peripherally and is 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] Multiple proposed mechanisms of nausea and vomiting involve various systems (eg, vestibular, gastrointestinal). Furthermore, these systems' specific pathways to stimulate nausea and vomiting are unclear. The precise locations and functions of nervous system structures involved in nausea and vomiting require further research. 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 5 muscarinic receptor subtypes, M1 through M5, show expression in the brain, and the roles of each subtype relative to nausea and vomiting remain unclear.[15][16][17][18]

Pharmacokinetics

Absorption: Following application behind the ear, scopolamine is absorbed transdermally, leading to detectable plasma concentrations within 4 hours and peaking at approximately 24 hours. After removing the transdermal system, some scopolamine remains in the skin layers and continues to be absorbed systemically.

Distribution: Scopolamine can penetrate the blood-brain barrier and reversibly bind to plasma proteins, influencing its distribution across various tissues within the body.

Metabolism: Scopolamine undergoes hepatic metabolism and conjugation.[19]

Elimination: After removing the transdermal system, plasma concentrations decrease gradually, with a half-life of 9.5 hours.

Administration

Available Dosage Forms and Strengths

The preferred method for administering 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 it is generally the specific patch used. As previously mentioned, oral scopolamine has demonstrated effectiveness when combined with the transdermal patch; however, this mode of administration is uncommon. Although the following administration methods appear in the published literature, patients should receive a specific plan based on their medical team’s assessment and clinical expertise. Before administering scopolamine, a thorough history and physical exam are necessary to rule out contraindications and accurately anticipate adverse effects.

Adult Dosage

Motion sickness: The patch is designed to release an initial priming dose to achieve steady-state concentrations in an acceptable amount of time. The patch then continues to release medication slowly, as discussed previously. The recommended protocol involves applying a scopolamine transdermal system to the hairless area behind the ear at least 4 hours before the anticipated onset of the antiemetic effect. This application is intended for use up to 3 days. When the therapeutic duration extends beyond this prescribed period, it is advised to exchange the initial transdermal system with a new one, positioning it behind the contralateral ear.

Postoperative nausea and vomiting: Regarding postoperative nausea and vomiting, specifically in surgeries excluding Cesarean sections, the optimal procedure entails placing a transdermal system behind the ear in the evening preceding the surgical intervention. Subsequently, the transdermal system is recommended to be removed 24 hours post-surgery. 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.

Importance of Hand Hygiene: A crucial element of the administration of scopolamine is counseling the patient and their family. In addition to remaining vigilant about adverse effects, anyone removing the patch must 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. After touching a scopolamine patch, patients should also be instructed to avoid touching their faces, especially their eyes. Many adverse effects of the scopolamine patch are due to contamination by the patient or by an individual changing or touching the patch.[2][3][5][15][16]

Specific Patient Populations

Hepatic impairment: The product labeling does not suggest dosage adjustments. Caution is advised due to the increased risks of adverse effects.

Renal impairment: No dosage adjustments are suggested in the product labeling due to the lack of specific studies. However, caution is advised due to increased risks of adverse effects.

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

Breastfeeding considerations: Limited data exists regarding the use of scopolamine during breastfeeding. Long-term scopolamine use may diminish milk production or letdown, but a single systemic dose is unlikely to interfere with breastfeeding. During prolonged use, monitor for indications of reduced lactation, such as insatiety and poor weight gain.[20]

Pediatric patients: Pediatric patients are susceptible to adverse reactions, including hallucinations, amblyopia, and mydriasis.

Older patients: Older patients are at an increased risk of and are more vulnerable to adverse anticholinergic effects due to differences in metabolism, excretion of medications, and changes in the CNS. In older patients, antimuscarinic medications may correlate with increased morbidity for several reasons, including increased risk of falls.[21][22][23][24][25] Scopolamine and antimuscarinic medications should be used very cautiously in older patients.[26]

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 significantly more common than ophthalmic symptoms. Scopolamine exerts a non-selective influence on all 5 muscarinic receptor subtypes (M1 to M5), raising the theoretical possibility of anticholinergic symptoms or anticholinergic syndrome.[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][27][28]

Common adverse drug reactions

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

Drug-Drug Interactions

Central nervous system depressants: Concurrent administration of scopolamine transdermal system with other substances inducing central nervous system (CNS) adverse events such as drowsiness, dizziness, or disorientation, like sedatives, hypnotics, opiates, anxiolytics, and alcohol, or those possessing anticholinergic properties such as other muscle relaxants, sedating antihistamines, tricyclic antidepressants may potentiate the effects of scopolamine. The choice between scopolamine and the interacting drug should be based on the patient's needs. If avoiding the interacting drug is not possible, continuous monitoring for CNS adverse reactions is recommended.

Drugs absorbed in the stomach: Scopolamine is an anticholinergic that can inhibit upper gastrointestinal motility, potentially altering the absorption rate of concurrently administered orally ingested drugs. Patients should be monitored for modifications in the therapeutic effect of concomitant orally administered medications with a narrow therapeutic index.

Interaction with gastric secretion test: Scopolamine interferes with gastric secretion testing. The scopolamine transdermal system should be discontinued 10 days before such tests are conducted.

Anticholinergic Drugs: Coadministration of scopolamine with other agents possessing anticholinergic properties heightens the risk of CNS adverse events, intestinal obstruction, and urinary retention.[29] Monitoring is advisable during scopolamine transdermal system treatment for patients concurrently using anticholinergic drugs.

Contraindications

The following are contraindications to scopolamine administration:

• Hypersensitivity to the medication or a component of the drug delivery system
• Acute angle closure glaucoma

Warning and Precautions

• Mydriasis: Mydriasis is a potential complication of scopolamine. Although reports exist of bilateral cases, the literature suggests that most 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][10]

• Glaucoma: 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 2 mechanisms. Aqueous humor becomes blocked from flowing from the posterior to the eye's anterior chamber, building up intraocular pressure. Patients may present with signs and symptoms such as nausea, vomiting, severe headache, severe ocular pain, blurred vision, red eyes, and dilation of the pupil. Glaucoma is an ophthalmic emergency that can result in blindness if untreated promptly, and an ophthalmology consultation is important.[30][31][32][33] A distinction should be made with patients with open-angle glaucoma, as these patients can safely use transdermal scopolamine patches.[34]

• Eclamptic seizures in pregnant individuals: Eclamptic seizures have been observed in those who are pregnant with severe preeclampsia following intravenous or intramuscular scopolamine administration. Avoid using the scopolamine transdermal system in patients with severe preeclampsia.[35]

• Gastrointestinal and urinary disorders: Due to its anticholinergic properties, scopolamine may decrease gastrointestinal motility and lead to urinary retention. Monitor patients more closely if they are suspected of intestinal obstruction, have pyloric or urinary bladder neck obstruction, or are using other anticholinergic drugs concurrently. Discontinue the scopolamine transdermal system if difficulty urinating develops.

• Drug withdrawal/post-removal symptoms: Discontinuing the scopolamine transdermal system, typically after a few days of use, may result in symptoms such as dizziness, nausea, abdominal cramps, headache, and muscle weakness. The onset of symptoms usually occurs 24 hours or more after the transdermal system is removed. Instruct patients to seek medical attention for severe symptoms.[36][37]

• Magnetic resonance imaging skin burns: The scopolamine transdermal system contains an aluminized film and skin burns have been reported during magnetic resonance imaging (MRI) scans.[38] Remove the scopolamine transdermal system before undergoing an MRI.

Monitoring

Blood pressure, heart rate, and temperature should be monitored in patients who receive scopolamine due to the possibility of adverse effects.[10] Intraocular pressure should also be recorded at baseline and follow-up.[39]

Toxicity

Signs and Symptoms of Overdose

Tachycardia, lethargy, convulsion, visual disturbance, dry flushed skin, dry mouth, urinary retention, agitation, coma, supraventricular arrhythmias, confusion, and hallucinations are signs and symptoms of anticholinergic toxicity.

Management of Overdose

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.[40][10][40] The patient then requires monitoring for a cholinergic crisis with atropine available at the bedside. As with most poisonings, vital signs and echocardiogram should be obtained and monitored.[41][42]

Enhancing Healthcare Team Outcomes

Postoperative nausea and vomiting is a ubiquitous presentation 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 and can lead to increased hospital admissions and unanticipated complications. Additionally, the prevention of PONV is vital to the patient's mental well-being. 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, is the proper approach to the prevention of PONV.[5] One potential antiemetic medication that has shown effectiveness in reducing the incidence of PONV is the transdermal scopolamine patch.[43]

Due to the scopolamine patch's pharmacokinetics and pharmacodynamics, it must be applied several hours before the start of the patient's surgery. The patch can also be applied the previous night. The patient's healthcare team must remain vigilant about identifying patients at high risk for PONV. 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 healthcare team must recognize these potential complications and begin management as soon as possible; this is especially true for older patients at increased risk of complications, including falls.[10][33][43][44][43]

A collaborative healthcare team approach is the best method for addressing PONV. Clinicians should accurately identify which patients will be candidates for antiemetic prophylaxis or therapy and coordinate with nurses and pharmacists for its delivery. Nurses will be administering the medication and should fully understand the points discussed in this activity regarding proper administration and handling of the drug, particularly in patch form. The pharmacist should complete a full drug-drug interaction check and verify dosing while also watching for mitigating factors like age that may require therapy modification. The pharmacist and nurse will 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. Finally, a common mechanism of ophthalmic symptoms from scopolamine is self-contamination by the patient. The interprofessional healthcare team, including the pharmacist, will 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]