(+-)-Tetrahydrozoline

BACKGROUND: We report two cases of drug-facilitated sexual assault which presented with CNS depression rendering the victims vulnerable to sexual assault and unable to recall the events surrounding the crimes. In each tetrahydrozoline (THZ) was quantified. CASE REPORT: Case #1 ingested an unknown amount of eye drops containing THZ mixed with alcoholic beverages. Case #1 presented to the emergency department (ED) approximately 7 hr after reportedly being sexually assaulted and was without symptoms in the ED. Earlier reports from individuals who saw her indicated the victim to be "heavily intoxicated". Case #2 also ingested an unknown amount of eye drops containing THZ mixed with alcoholic beverages. Case #2 presented to an ED without symptoms approximately 23 hr after reportedly being sexually assaulted. Urine obtained from both cases was assessed for THZ concentrations using gas-chromatography-mass spectrometry. CASE DISCUSSION: Case #1 had a 0.15 g% (by weight by volume) urine ethanol concentration and a urinary THZ concentration of 1.481 ng/mL, approximately 7h after ingestion. Case #2 was negative for ethanol but had a urine THZ concentration of 108 ng/mL at 23 hr post-ingestion. Few case reports have been published documenting the use of THZ to facilitate sexual assault. CONCLUSION: We report two cases of drug-facilitated sexual assault involving the use of THZ where alcoholic beverages were concomitantly consumed. This is the first paper to our knowledge which discusses pharmacology of THZ ingestion and the significance of alcohol being present.

IDENTIFICATION AND USE: Tetrahydrozoline hydrochloride, an imidazoline derivative, is applied topically to the eye for self-medication to temporarily relieve congestion, itching, and minor irritation, and to control hyperemia in patients with superficial corneal vascularity. Ocular decongestants are ineffective in the treatment of delayed hypersensitivity reactions such as contact dermatoconjunctivitis. The vasoconstrictor effect of tetrahydrozoline may be used during some ocular diagnostic procedures, but some clinicians prefer phenylephrine to tetrahydrozoline for this use. HUMAN STUDIES: Serious adverse events requiring hospitalization have been reported in pediatric patients following accidental ingestion of nonprescription ophthalmic solutions or nasal sprays containing imidazoline derivatives including tetrahydrozoline. Between 1985 and October 2012, 96 cases of accidental ingestion were reported in children 1 month to 5 years of age. The amount of drug ingested ranged from 0.6-45 mL. While no deaths were reported, more than half of these cases reported serious adverse events requiring hospitalization, including nausea, vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, hypertension, sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma. ANIMAL STUDIES: In dogs, signs of intoxication may include vomiting, bradycardia, cardiac arrhythmias, poor capillary refill time, hypotension or hypertension, panting, increased upper respiratory sounds, depression, weakness, nervousness, hyperactivity, or shaking. These signs appear within 30 min to 4 hr postexposure. In general, imidazoline decongestant exposure may affect the GI, cardiopulmonary, and nervous systems.

/HUMAN EXPOSURE STUDIES/ The mydriatic effect of three ocular decongestants, containing 0.1% tetrahydrozoline hydrochloride, 0.3% chlorpheniramine maleate, and 0.05% tetrahydrozoline hydrochloride in combination with 0.3% pheniramine maleate, respectively, was evaluated in 10 healthy volunteers. The study was carried out using a single dose of the tested drug, instilling 2 drops in one eye and 2 drops of a placebo in the other. The papillary diameters were measured by photographic pupillography under basal conditions and 15, 30, 45, 60, 90, and 120 min after each treatment. Near and distance visual acuity and tonometry were evaluated under basal conditions and 50 and 95 min after instillation of drugs. No statistical significant differences between the treated and the control pupil diameters were found after instillation of 0.1% tetrahydrozoline hydrochloride or 0.3% chlorpheniramine maleate. The combination of 0.05% tetrahydrozoline hydrochloride with 0.3% pheniramine maleate caused a significant mydriasis from 30 min up to 120 min (p < 0.01 and p < 0.0005) after instillation, more pronounced in light irides. No local and systemic effects and no effects on visual acuity and ocular pressure were detected. On the basis of our results, it is possible to conclude that the persistent mydriatric action of the two-drug combination is due to a synergism; the use of these eyedrops should be avoided in subjects with narrow-angle glaucoma, light irides, narrow iridocorneal angle, and low anterior chamber for the risk of ocular pressure increase.

/SIGNS AND SYMPTOMS/ The mechanism of action of tetrahydrozoline has not been conclusively determined. Most pharmacologists believe that the drug directly stimulates a-adrenergic receptors of the sympathetic nervous system and exerts little or no effect on beta-adrenergic receptors. Following topical application of tetrahydrozoline to the conjunctiva, small arterioles are constricted and conjunctival congestion is temporarily relieved, but reactive hyperemia may occur. The drug also may produce mydriasis when applied to the conjunctiva, but this effect is usually minimal with the concentrations used as ocular decongestants.

/SIGNS AND SYMPTOMS/ OBJECTIVES: To study acute exposure to imidazoline derivatives in 72 children younger than 15 years of age, followed-up from January 1994 to December 1999. METHODS: This is a retrospective study of 72 patients with age between 2 months and 13 years (median 2 years; 25-75% = 1 to 3 years old) exposed to naphazoline (N = 48), fenoxazoline (N = 18), oxymetazoline (N = 5) and tetrahydrozoline (N = 1), through oral (N = 46), nasal (N = 24) or unknown (N = 2) routes. RESULTS: Fifty-seven children developed clinical manifestations such as somnolence (N = 34/57), sweating (N = 20/57), pallor (N = 17/57), hypothermia (N = 16/57), bradycardia (N = 13/57), cool extremities (N = 9/57), restlessness (N = 7/57), tachycardia (N = 6/57), vomiting (N = 5/57), irregular respiratory pattern and apnea (N = 5/57), miosis/mydriasis (N = 4/57). Naphazoline was the active ingredient most frequently involved (N = 47), followed by fenoxazoline (N = 5) and oxymetazoline (N = 4). The onset of clinical manifestations was rapid, beginning within 2 hours after exposure in 32/57 children. Only supportive measures were employed, with one child requiring mechanical ventilation after accidental naphazoline ingestion. In most of the children resolution of symptoms occurred within 24 hours (N = 39/57). No deaths were observed. Patients exposed to naphazoline (N = 47/48) presented a higher frequency of clinical signs of poisoning in comparison with those exposed to fenoxazoline (N = 5/18) (p < 0.001). There were no significant differences in the frequency of patients who presented clinical manifestations considering the route of exposure [oral (N = 34/46), nasal (N = 21/24); p = 0.31]. CONCLUSIONS: Most children (especially those younger than 3 years) exposed to imidazoline derivatives (especially naphazoline) presented early signs of poisoning regardless of the exposure route (nasal or oral). The main signs observed were nervous system, cardiovascular and respiratory depression. Most children showed complete resolution of the symptoms within 24 hours.

/ALTERNATIVE and IN VITRO TESTS/ We have investigated in the isolated, perfused guinea pig heart whether a alpha-adrenergic imidazolines, tolazoline and tetrahydrozoline stimulate histamine H2-receptors directly or via the release of endogenous histamine. At 30 degrees C neither tolazoline nor tetrahydrozoline released histamine. However, both increased heart rate, contractility, and decreased coronary vascular resistance as a function of dose. The H2-receptor antagonists cimetidine and tiotidine blocked the effects of tolazoline and tetrahydrozoline. The actions of tetrahydrozoline were confined to its 1-isomer. At 37 degrees C tolazoline, but not tetrahydrozoline, released histamine into the coronary perfusate. The maximum tolazoline-induced change in heart rate was 2.5-3.0 times greater than tetrahydrozoline's, in distinct contrast to their identical effect at 30 degrees C. All other responses to the two drugs were the same at 30 and 37 degrees C. Our results suggest that tolazoline and tetrahydrozoline directly stimulate histamine H2-receptors. Because of the differences in the structures of imidazolines and histamine, these findings have implications for the current hypothesis regarding histamine H2-receptor activation.

/VETERINARY STUDIES/ Toxicity from human drugs: The imidazoline derivatives, oxymetazoline, xylometazoline, tetrahydrozoline and naphazoline are found in topical ophthalmic and nasal decongestants available OTC. ... In dogs, signs of intoxication may include vomiting, bradycardia, cardiac arrhythmias, poor capillary refill time, hypotension or hypertension, panting, increased upper respiratory sounds, depression, weakness, nervousness, hyperactivity, or shaking. These signs appear within 30 min to 4 hr postexposure. In general, imidazoline decongestant exposure may affect the GI, cardiopulmonary, and nervous systems.

Patients with glaucoma should be advised not to use tetrahydrozoline ophthalmic solutions except under the advice and supervision of a physician. Ophthalmic solutions of the drug should not be used in patients with angle-closure glaucoma or other serious eye diseases.

Tetrahydrozoline hydrochloride is contraindicated in children younger than 2 years of age. Ophthalmic solutions of tetrahydrozoline should not be used for self-medication in children younger than 6 years of age.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/VET:/ Decontamination may not be practical due to the rapid absorption and onset of clinical signs. Heart rate and rhythm and blood pressure should be assessed, and an ECG obtained if needed. IV fluids should be given, along with atropine ... , if bradycardia is present. Diazepam ... can be given if CNS signs (eg, apprehension, shaking) are present. Serum electrolytes (ie, potassium, sodium, chloride) should be assessed and corrected as needed. Yohimbine, which is a specific alpha2-adrenergic antagonist, can also be used ... if needed. If yohimbine is not available, atipamezole can be used ... . /Imidazoline decongestants/

Ophthalmic vasoconstrictors. The active ingredient of the product consists of one of the following, within the established concentration for each ingredient: Tetrahydrozoline hydrochloride, 0.01 to 0.05 percent. /Tetrahydrozoline hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tetrahydrozoline hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tetrahydrozoline hydrochloride/

Ophthalmic Solutions; Sympathomimetics; Nasal Decongestants

MEDICATION

Use (kg; approx.) in Germany (2009): >10

Tetrahydrozoline ... is made by the condensation of 1,2,3,4-tetrahydro-1-naphthoic acid or its methyl ester with 1,2-ethylenediamine.

Preparation from ethylenediamine, ethylenediamine hydrochloride, and methyl 1,2,3,4-tetrahydro-1-naphthoate: Synerholm et al., United States of America patent 2731471 (1956 to Sahyun Labs.)

Table: Tetrahydrozoline Hydrochloride Preparations [Table#7131]

Table: Tetrahydrozoline Hydrochloride Combinations Preparations [Table#7132]