Emesis

In emesis the stomach empties in a retrograde manner. The pyloric sphincter is closed while cardia and esophagus relax to allow gastric contents to be propelled orad by a forceful synchronous contraction of abdominal wall muscles and diaphragm. Closure of the glottis and elevation of the soft palate prevent entry of vomitus into the trachea and the nasopharynx. As a rule, there is prodromal salivation or yawning. Coordination between these different stages depends on the medullary center for emesis, which can be activated by diverse stimuli. These are conveyed via the vestibular apparatus, visual, olfactory, and gustatory inputs, as well as viscerosensory afferents from the upper alimentary tract. Psychic stress may also activate the emetic center. The mechanisms underlying motion sickness (kinetosis, sea sickness) and vomiting during pregnancy are still unclear.

Polar substances cannot reach the emetic center itself because it is protected by the blood–brain barrier. However, they can indirectly excite the center by activating chemoreceptors in the area postrema or receptors on peripheral vagal nerve endings.

Antiemetic therapy. Vomiting can be a useful reaction enabling the body to eliminate an orally ingested poison. Antiemetic drugs are used to prevent kinetosis, pregnancy vomiting, cytotoxic drug-induced or postoperative vomiting, as well as vomiting due to radiation therapy.

Motion sickness. Effective prophylaxis can be achieved with the parasympatholytic scopolamine (p.110) and H1-antihistaminics (p.118) of the diphenylmethane type (e. g., diphenhydramine, meclizine). Antiemetic activity is not a property shared by all parasympatholytics or antihistaminics. The ef - cacy of the drugs mentioned depends on the actual situation of the individual (gastric filling, ethanol consumption), environmental conditions (e. g., the behavior of fellow trav-

elers), and the type of motion experienced. The drugs should be taken 30 minutes before the start of travel and repeated every 4–6 hours. Scopolamine applied transdermally through an adhesive patch 6–8 hours before travel can provide effective protection for up to 3 days.

Pregnancy vomiting is prone to occur in the first trimester; thus, pharmacotherapy would coincide with the period of maximal fetal vulnerability to chemical injury. Accordingly, antiemetics (antihistaminics, or neuroleptics if required; p. 232) should be used only when continuous vomiting threatens to disturb electrolyte and water balance to a degree that places the fetus at risk.

Drug-induced vomiting. To prevent vomiting during anticancer chemotherapy (especially, with cisplatin), effective use can be made of 5-HT3 receptor antagonists (e. g., ondansetron, granisetron, and tropisetron), alone or in combination with glucocorticoids (methylprednisolone, dexamethasone). Anticipatory nausea and vomiting, resulting from inadequately controlled nausea and emesis in patients undergoing cytotoxic chemotherapy, can be attenuated by a benzodiazepine such as lorazepam. Dopamine ag- onist-induced nausea in parkinsonian patients (p.188) can be counteracted with D2- receptor antagonists that penetrate poorly into the CNS (e. g., domperidone, sulpiride).

Metoclopramide is effective in nausea and vomiting of gastrointestinal origin (5-HT4 receptor agonism) and at high dosage also in chemotherapy- and radiation-induced sickness (low potency antagonism at 5-HT3 and D3-receptors). Phenothiazines (e. g., levomepromazine, trimeprazine, and perphenazine) or metoclopramide may suppress nausea/emesis that follows certain types of surgery or is due to opioid analgesics, gastrointestinal irritation, uremia, and diseases accompanied by elevated intracranial pressure.

The synthetic cannabinoids dronabinol and nabilone have antiemetic effects that may benefit AIDS and cancer patients.

H3C Parasympatholytics

N

OCH2OH

O C CH

O Scopolamine

H1-Antihistamines

CH3

CH O CH2 CH2 N

CH3

Diphenhydramine

Cl

Meclozine

CH N N CH2

CH3

Alcohol Abuse

Since prehistoric times, ethanol-containing beverages have enjoyed widespread use as a recreational luxury. What applies to any medicinal substance also holds for alcohol: the dose alone makes the poison (see p. 2). Excessive, long-term consumption of alcoholic drinks, or alcohol abuse, is harmful to the affected individual. Alcoholism must be considered a grave disorder that plays a major role in terms of numbers alone; for instance, in Germany 1 000 000 people are affected by this self-inflicted illness.

Ethanol is miscible with water and is well lipid-soluble, enabling it to penetrate easily through all barriers in the organism; the blood–brain barrier and the placental barrier are no obstacles. In liver cells, alcohol is broken down to acetic acid via acetaldehyde (A). Ethyl alcohol is never ingested as a chemically pure substance but in the form of an alcoholic beverage that contains flavoring agents and higher alcohols, depending on its origin. The effect desired by the consumer takes place in the brain: ethanol acts as a stimulant, it disinhibits, and it enhances sociability, as long as the beverage is enjoyed in moderate quantities. After higher doses, self-critical faculties are lost and motor function is impaired–the familiar picture of the drunk. Still higher doses induce a comatose state (caution: hypothermia and respiratory paralysis). The complex effects on the CNS cannot be ascribed to a simple mechanism of action. An inhibitory effect on the NMDA subtype of glutamate receptor appears to predominate.

In chronic alcohol abuse, mainly two organs are damaged:

1.In the liver, hepatocytes may initially undergo fatty degeneration, this process being reversible. With continued exposure, liver cells die and are replaced by connective tissue newly formed from myofibroblasts: liver cirrhosis. Hepatic blood flow is greatly reduced; the organ becomes unable to fulfill its detoxification

function (danger of hepatic coma). Collateral circulation routes develop (bleeding from esophageal varicose veins) with production of ascites. Alcoholic liver cirrhosis is a severe, mostly progressive disease that permits only symptomatic therapy (B).

2.The functional capacity of the brain is impaired. Irreversible damage may manifest in a measurable fallout of neuronal cell bodies. Often delirium tremens develops (usually triggered by alcohol withdrawal), whichcanbemanagedwithintensivetherapy (clomethiazole, haloperidol, among others). In addition, alcoholic hallucinations and Wernicke–Korsakow syndrome

occur. All of these are desolate states.

It must be pointed out specifically that alcohol abuse during pregnancy leads to (em- bryo–fetal alcohol syndrome (malformations, persistent intellectual deficits). This intrauterine intoxication is relatively common: one case per 1000 births (C).

Chronic alcohol abuse is an expression of true dependence. Thus, therapy of this addiction is dif cult and frequently without success. There is no pharmacotherapeutic silver bullet (the NMDA receptor antagonist acamprosate may be worth trying). Above all, psychotherapeutic care, a change in milieu, and supportive treatment with benzodiazepines are important.

Main catabolic pathway of ethanol in liver cell

Quotient NADH/NAD+

Fatty acid oxidation Fatty acid synthesis Triglyceride synthesis

Fatty liver

Cell necroses

Cirrhosis