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

Local Treatment of Glaucoma

Currently, glaucoma therapy remains focused on mechanisms designed to decrease intraocular pressure (IOP) and this approach is considered effective also in normal tension glaucoma.

Normal values of IOP lie between 15 and 20 mmHg, that is, above the venous pressure. IOP reflects the ratio of production and outflow of aqueous humor. Aqueous humor is secreted by the epithelial cells of the ciliary body and, following passage through the trabecular meshwork, is drained via the canal of Schlemm (blue arrows in A). This route is taken by 85–90% of aqueous humor; a smaller portion enters the uveoscleral vessels and, thus, the venous system. In the socalled open-angle glaucoma, passage of aqueous humor through the trabecular meshwork is impeded so that drainage through Schlemm’s canal becomes inef - cient. The much rarer primary angle-closure glaucoma features a narrowed iridocorneal angle or a tight contact between iris and lens (‘pupillary block’). Secondarily, blockade by the iris of the trabecular meshwork may be due to various causes (e. g., synechiae). Topographical relationships in the chamber angle are shown enlarged in the red box.

For topical therapy of open-angle glaucoma, the following groups of drugs can be used: for reducing production of aqueous humor, β-blockers (e. g., timolol), α2-agonists (clonidine, brimonidine), and inhibitors of carbonic anhydrase (dorzolamide, brinzolamide).

For promoting drainage through the trabecular meshwork, parasympathomimetics (e. g., pilocarpine) are effective, and through the uveoscleral route, prostaglandin derivatives. Pilocarpine excites the ciliary muscle and the pupillary sphincter. The contraction of both muscles widens the geometrical arrangement of trabeculae, resulting in improved drainage of aqueous humor. Uveoscleral drainage is augmented by the prostaglandin derivatives lanatoprost and bimato-

prost. Both substances can be used for topical monotherapy or combined with other active principles. A peculiar side effect is notable: dark pigmentation of iris and eyelashes.

The therapy of angle-closure glaucoma involves chiefly reduction of aqueous humor production (osmotic agents, β-blockers) and surgical procedures.

The topical application of pharmaceuticals in the form of eye-drops is hampered by a pharmacokinetic problem. The drug must penetrate from the ocular surface (cornea and conjunctiva) to its target sites, namely, the smooth muscle of the ciliary body or the iris, the secretory epithelium of the ciliary body, or the uveoscleral vessels (B). The applied drug concentration is diluted by lacrimal fluid and drains via the tear duct to the nasal mucosa, where the drug may be absorbed. During permeation through the cornea, transport through blood vessels takes place. The drug concentration reaching the anterior chamber is diluted by aqueous humor and, finally, drug molecules are also transported away via Schlemm’s canal. In order to reach the required concentrations at the target site (10–8 to 10–6 M, depending on the substance), the concentration needed in the eye drops is ~ 10–2 M (equivalent to ~ 0.5 mg per droplet, depending on molecular weight). The amount of drug contained in a single drop is large enough to elicit a general reaction with systemic use. Even when applied properly, eye drops can therefore evoke side effects in the cardiovascular system or the bronchial space. This possibility leads to corresponding contraindications. Thus, in patients with severe congestive heart failure, bradycardia, or obstructive lung disease, eye drops containing β-block- ers must be avoided at all times.

A. Local pharmacotherapy of glaucoma

Conjunctiva

Increased drainage

Pilocarpine

Prostaglandin derivatives

Schlemm’s canal

Cornea

Iris

Sclera

M. ciliaris

Proc. ciliaris

Inhibitors of aqueous humor production: β -Blocker, CAH-inhibitors, α 2-agonist