HEALTH AND MEDICAL PRODUCTS:MOTION SICKNESSTR EATMENTS.

MOTION SICKNESSTR EATMENTS

Motion sickness is a very common disturbance caused by repeated expo- sure to such motions as the swell of the sea, the movement of a car, or the turbulence of a plane in flight. Although many ancient seafaring nations were familiar with this malady over thousands of years, motion sickness has become increasingly prevalent with the many forms of vehicular travel currently available. Names including seasickness, airsickness, car- sickness, train sickness, amusement park ride sickness, flight simulator sickness, and space motion sickness provide an indication of the many causes of this ailment. Characteristically, motion sickness is usually “experienced” by initially sensing gastric discomfort, followed by increased salivation, eructation (belching), and a feeling of general bodily warmth. When continually exposed to a motion sickness-triggering stimulus, nor- mal digestion is decreased and the symptoms of nausea, pallor, and sweating are all increased. Eventually, vomiting or retching occurs. Interestingly, the word “nausea” is derived from the Greek word for ship (naus). Another distinct syndrome of motion sickness that lacks gastrointestinal complaints usually includes drowsiness, headache, generalized discomfort (malaise), and various changes in mental perspective. Sufferers have been known to experience a psychological shift in attitude from one of happy excitement to apathy, depression, and nearly suicidal despair in a very short time.

The sensation of balance, and thus the ability to maintain equilibrium, is regulated by a complex interaction of bodily systems that includes the inner ears, the eyes, skin pressure receptors, muscle and joint sensory receptors, and the CNS (brain and spinal cord). The cause of motion sick- ness is generally considered to be a mismatch of visual and inner ear sensations. The eyes observe where the body is in space (e.g., upside down, right side up, etc.) and also directions of motion. Within the inner ear, these sensations pertain specifically to the vestibular complex, including the vestibule (which includes a pair of membranous sacs contain- ing receptors for the sensation of gravity and linear acceleration) and the semicircular canals (which contain ducts with receptors that are stimulated by rotation of the head and detect angular acceleration). The CNS receives visual and vestibular sensory information and “compares” the inputs with the individual’s expectations of motion derived from previous experiences. Motion sickness tends to manifest when central processing stations, such as within the brainstem (including the midbrain, pons, and medulla oblongata), receive conflicting sensory inputs from the vestibular and visual systems (e.g., the vestibular complex detects motion while the passenger is flying in a plane experiencing air turbulence, but the eyes do not detect motion at all as only the inside of the plane is visualized). Motion sickness occurs most commonly with acceleration (for- ward and backward) in a direction perpendicular to the longitudinal axis of the body (especially when head movements occur away from the direction of motion, as when turning the head backward to face the back- seat of a forward-moving car) and with slow-moving vertical (up and down) oscillatory motion called heave (e.g., on camelback or onboard ships). Motion sickness symptoms tend to subside after thirty-six to seventy-two hours of continuous exposure but may return on exposure to the “preexposure” environment until readaptation takes place (this is called mal de debarquement syndrome, or arrival sickness).

Nausea and vomiting (also called emesis; from the Greek word emetikos meaning inclined to vomit) are the most common complaints of motion sickness and are mediated by CNS chemical messengers called neurotransmitters. In response to visual and vestibular input, increased levels of dopamine stimulate the medulla oblongata’s chemoreceptive trigger zone, which in turn stimulates the vomiting center (VC) located within the reticular formation of the brainstem. The chemoreceptive trigger zone is extremely sensitive to the actions of drugs and chemical toxins, mainly because it is not protected by the blood-brain barrier. The VC is also directly stimulated by inputs from the vestibular complex via the vestibular nuclei (a grouping of nerve cell bodies) positioned be- tween the pons and the medulla oblongata and by increased levels of the neurotransmitter acetylcholine. The VC and vestibular nuclei contain muscarinic cholinergic receptors, while the vestibular nuclei also contain histamine H1 receptors (H1). The name “muscarinic” indicates that the receptor can be stimulated by muscarine, a toxin produced by some poisonous mushrooms (e.g., Amanita muscaria).

Most over-the-counter products that are marketed for the prevention or amelioration of motion sickness contain active antiemetic (drugs that prevent nausea and/or vomiting) ingredients, including anticholinergics or antihistamines. When used specifically to prevent motion sickness, these antiemetic medicines generally are most effective if administered well be- fore the motion activity takes place. However, the precise action of these medications in preventing motion sickness is unclear. Histamine receptor 1 antagonist drugs typically act as antihistamines by reversibly competing with free histamine for binding at H1 receptor sites. In addition, these drugs may also act as anticholinergics/antimuscarinics by competitively antagonizing the binding of acetylcholine at muscarinic receptor sites on postsynaptic neurons. Anticholinergics inhibit the effect of acetylcholine, which normally controls the contraction of skeletal muscles and also plays an important role in the chemistry of the brain and peripheral ner- vous system. Anticholinergics block acetylcholine stimulation of motility and secretions throughout the entire gastrointestinal tract. In addition, H1 antagonists block neural pathways originating in the vestibular com- plex and antagonize muscarinic cholinergic receptors.

Examples of antihistamines used to prevent and treat the nausea, vom- iting, and dizziness associated with motion sickness include meclizine HCl, cyclizine HCl, diphenhydramine HCl, and dimenhydrinate. Meclizine HCl (1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine dihydrochloride monohydrate; C25H27ClN2 X 2(H-Cl)x H2O) and cycli- zine HCl (1-diphenylmethyl-4-methylpiperazine hydrochloride; C18H22N2· ClH) are both piperazine-derivative antihistamines. The antiemetic ef- fect of meclizine HCl is thought to be mediated through the chemore- ceptive trigger zone of the medulla oblongata and by the general blocking of muscarinic receptors within the CNS. Cyclizine HCl is believed to block the H1 and muscarinic receptors associated with the VC, reducing the sensitivity of, and the activity along, the pathway that involves the transmission of nerve impulses from the vestibular complex of the inner ear to the VC. Cyclizine HCl also increases lower esophageal sphincter tone and relaxes the smooth muscles in the stomach directly to prevent eme- sis. The VC can also receive many excitatory inputs from nerve endings of vagus nerve (cranial nerve X) sensory fibers within the gastrointestinal tract.

Ethanolamine-derivative H1 antagonist antihistamines used to treat mo- tion sickness include diphenhydramine HCl [2-(diphenylmethoxy)-N,N- dimethylethylamine hydrochloride; C17H21NO·HCl] and dimenhydrinate [8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione compound with 2-(diphenylmethoxy)-N,N-dimethylethanamine (1:1); C24H28ClN5O3]. Diphenhydramine HCl provides a competitive reversible blockade of muscarinic receptors, thereby inhibiting cholinergic neurotransmission via acetylcholine at muscarinic receptor sites and acting as an antiemetic. It stabilizes the motion-sensitive vestibular complex balance center in the inner ear, thus stopping or preventing the sensation of imbalance caused by effects on the CNS. Dimenhydrinate, a combination of diphenhy- dramine and chlorotheophylline, also possesses anticholinergic activity and has been shown to depress inner ear vestibular function. Although the exact antiemetic mechanism is unknown, dimenhydrinate, as an H1 antagonist antihistamine, has been shown to be effective in treating mo- tion sickness by acting as a central antagonist of acetylcholine (anticholinergic). This drug blocks excitatory impulses originating in the vestibular complex of the inner ear at cholinergic synapses in the region of the vestibular nuclei of the brainstem.

Currently, the most popular anticholinergic agent used to treat motion sickness is the centrally acting antimuscarinic/anticholinergic drug called scopolamine hydrobromide (or hyoscine hydrobromide; C17H21NO4·HBr). An atropine derivative, it is an alkaloid drug obtained from plants of the nightshade family (Solanaceae), chiefly from black henbane (Hyoscyamus niger). This drug is delivered via a cutaneous patch consisting of a drug reservoir that contains scopolamine, mineral oil, and polyisobutylene (elastomer, or synthetic rubber; C4H8) sandwiched between polyester film and an adhesive layer. This dime-sized patch is applied to an area of intact, dry, and hairless skin behind the ear and delivers a slowly ab- sorbed continuous dose of scopolamine into the systemic blood circula- tion for three days. Structurally similar to acetylcholine, scopolamine prevents motion-induced nausea by interfering with the transmission of nerve impulses by acetylcholine at muscarinic receptors, thereby inhibiting inner ear vestibular nerve stimulation and decreasing nerve transmission and communication to the vestibular cerebellar pathway that terminates in the CNS. This action results in inhibition of the vomiting reflex. Since scopolamine crosses the blood-brain barrier, it may also have a direct action on the VC muscarinic receptors within the brainstem. It also reduces spasms of the digestive system, bladder, and urethra that often accompany the feelings of motion sickness and nausea.