defopan

Uses

defopan is a belladonna alkaloid with anticholinergic effects indicated for the treatment of nausea and vomiting associated with motion sickness and postoperative nausea and vomiting (PONV).

defopan is indicated in adult patients for the prevention of nausea and vomiting associated with motion sickness and for the prevention of postoperative nausea and vomiting (PONV) associated with anesthesia or opiate analgesia.

defopan is also used to associated treatment for these conditions: Motion Sickness, Post Operative Nausea and Vomiting (PONV), Preanesthetic medication therapy

How defopan works

Acetylcholine (ACh) is a neurotransmitter that can signal through ligand-gated cation channels (nicotinic receptors) and G-protein-coupled muscarinic receptors (mAChRs). ACh signalling via mAChRs located in the central nervous system (CNS) and periphery can regulate smooth muscle contraction, glandular secretions, heart rate, and various neurological phenomena such as learning and memory. mAChRs can be divided into five subtypes, M1-M5, expressed at various levels throughout the brain. Also, M2 receptors are found in the heart and M3 receptors in smooth muscles, mediating effects apart from the direct modulation of the parasympathetic nervous system. While M1, M3, and M5 mAChRs primarily couple to G_q proteins to activate phospholipase C, M2 and M4 mainly couple to G_i/o proteins to inhibit adenylyl cyclase and modulate cellular ion flow. This system, in part, helps to control physiological responses such as nausea and vomiting.

defopan acts as a non-selective competitive inhibitor of M1-M5 mAChRs, albeit with weaker M5 inhibition; as such, scopolamine is an anticholinergic with various dose-dependent therapeutic and adverse effects. The exact mechanism(s) of action of scopolamine remains poorly understood. Recent evidence suggests that M1 (and possibly M2) mAChR antagonism at interneurons acts through inhibition of downstream neurotransmitter release and subsequent pyramidal neuron activation to mediate neurological responses associated with stress and depression. Similar antagonism of M4 and M5 receptors is associated with potential therapeutic benefits in neurological conditions such as schizophrenia and substance abuse disorders. The significance of these observations to scopolamine's current therapeutic indications of preventing nausea and vomiting is unclear but is linked to its anticholinergic effect and ability to alter signalling through the CNS associated with vomiting.

Toxicity

defopan overdose may manifest as lethargy, somnolence, coma, confusion, agitation, hallucinations, convulsion, visual disturbance, dry flushed skin, dry mouth, decreased bowel sounds, urinary retention, tachycardia, hypertension, and supraventricular arrhythmias. In some cases, overdose symptoms may appear similar to those associated with withdrawal following discontinuation. However, withdrawal symptoms such as bradycardia, headache, nausea, abdominal cramps, and sweating can help to distinguish between these possibilities. Overdose management primarily involves the removal of all transdermal patch systems combined with symptomatic and supportive care. Ensuring an adequate airway, supplemental oxygen, establishing intravenous access, and continuous monitoring are recommended. In cases where patients have swallowed one or more patch systems, it may be necessary to remove them or administer activated charcoal.

Animal studies revealed an oral LD₅₀ of 1880 mg/kg in mice and 1270 mg/kg in rats, and a subcutaneous LD₅₀ of 1650 mg/kg in mice and 296 mg/kg in rats.

Food Interaction

• Avoid grapefruit products. Coadministration of scopolamine with grapefruit juice has been shown to delay scopolamine absorption and increase its bioavailability without altering its elimination.

[Minor] The coadministration with grapefruit juice may delay the absorption and increase the bioavailability of oral scopolamine.

The proposed mechanism is delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits.

In an open-label, crossover study consisting of 14 subjects, the consumption of grapefruit juice (compared to water) was associated with a 30% increase in mean systemic bioavailability and a 153% increase in time to reach peak serum concentration (Tmax) of scopolamine.

However, the perceived pharmacodynamic effect of the drug, as measured by % change in subjective alertness compared to baseline, was similar after coadministration with water and grapefruit juice.

Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of of scopolamine but may delay its onset of action following oral administration.

However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability.

defopan Alcohol interaction

[Moderate] GENERALLY AVOID:

Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous.

In addition, the potential for abuse may be increased with the combination.

The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system.

No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load.

However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

Alcohol should generally be avoided during therapy with anticholinergic agents.

Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

defopan Hypertension interaction

[Minor] Cardiovascular effects of anticholinergics may exacerbate hypertension.

Therapy with anticholinergic agents should be administered cautiously in patients with hypertension.

defopan Drug Interaction

Moderate: lorazepam, diphenhydramine, pregabalin, acetaminophen / hydrocodone, promethazine, metoclopramide, alprazolam, sertralineMinor: acetaminophen, acetaminophenUnknown: amphetamine / dextroamphetamine, fluticasone nasal, polyethylene glycol 3350, pantoprazole, montelukast, cyanocobalamin, ascorbic acid, cholecalciferol, ondansetron, cetirizine

defopan Disease Interaction

Major: autonomic neuropathy, GI obstruction, glaucoma, obstructive uropathy, reactive airway diseases, myasthenia gravis, infectious diarrheaModerate: cardiac disease, tachycardia, coronary artery disease, gastric ulcer, gastroesophageal reflux, ulcerative colitisMinor: hypertension, hyperthyroidism, diarrhea, fever

Volume of Distribution

The volume of distribution of scopolamine is not well characterized. IV infusion of 0.5 mg scopolamine over 15 minutes resulted in a volume of distribution of 141.3 ± 1.6 L.

Elimination Route

The pharmacokinetics of scopolamine differ substantially between different dosage routes. Oral administration of 0.5 mg scopolamine in healthy volunteers produced a C_max of 0.54 ± 0.1 ng/mL, a t_max of 23.5 ± 8.2 min, and an AUC of 50.8 ± 1.76 ng*min/mL; the absolute bioavailability is low at 13 ± 1%, presumably because of first-pass metabolism. By comparison, IV infusion of 0.5 mg scopolamine over 15 minutes resulted in a C_max of 5.00 ± 0.43 ng/mL, a t_max of 5.0 min, and an AUC of 369.4 ± 2.2 ng*min/mL.

Other dose forms have also been tested. Subcutaneous administration of 0.4 mg scopolamine resulted in a C_max of 3.27 ng/mL, a t_max of 14.6 min, and an AUC of 158.2 ng*min/mL. Intramuscular administration of 0.5 scopolamine resulted in a C_max of 0.96 ± 0.17 ng/mL, a t_max of 18.5 ± 4.7 min, and an AUC of 81.3 ± 11.2 ng*min/mL. Absorption following intranasal administration was found to be rapid, whereby 0.4 mg of scopolamine resulted in a C_max of 1.68 ± 0.23 ng/mL, a t_max of 2.2 ± 3 min, and an AUC of 167 ± 20 ng*min/mL; intranasal scopolamine also had a higher bioavailability than that of oral scopolamine at 83 ± 10%.

Due to dose-dependent adverse effects, the transdermal patch was developed to obtain therapeutic plasma concentrations over a longer period of time. Following patch application, scopolamine becomes detectable within four hours and reaches a peak concentration (t_max) within 24 hours. The average plasma concentration is 87 pg/mL, and the total levels of free and conjugated scopolamine reach 354 pg/mL.

Half Life

The half-life of scopolamine differs depending on the route. Intravenous, oral, and intramuscular administration have similar half-lives of 68.7 ± 1.0, 63.7 ± 1.3, and 69.1 ±8/0 min, respectively. The half-life is greater with subcutaneous administration at 213 min. Following removal of the transdermal patch system, scopolamine plasma concentrations decrease in a log-linear fashion with a half-life of 9.5 hours.

Clearance

IV infusion of 0.5 mg scopolamine resulted in a clearance of 81.2 ± 1.55 L/h, while subcutaneous administration resulted in a lower clearance of 0.14-0.17 L/h.

Elimination Route

Following oral administration, approximately 2.6% of unchanged scopolamine is recovered in urine. Compared to this, using the transdermal patch system, less than 10% of the total dose, both as unchanged scopolamine and metabolites, is recovered in urine over 108 hours. Less than 5% of the total dose is recovered unchanged.

Innovators Monograph

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