Common side effects of the adrenergic drugs are fear, anxiety, tenseness, restlessness, headache, weakness, tremor, dizziness, pallor, and awareness of heartbeat. They are usually tem­porary and subside with rest and reassurance. Respiratory difficulty rarely occurs in neurotic patients. Existing symptoms can be aggra­vated. The most common negative effect of metaproterenol, salbu­tamol, or terbutaline is tremor. Aggravation of high blood pressure is more likely with drugs that affect the blood vessels and heart, but blood pressure may increase with use of any drug in this group. Meta­proterenol, salbutamol, or terbutaline rarely cause low blood pressure. They can also induce nausea, vomiting, and difficulty urinating. Patients suffering from high blood pressure, thyroid disease, or heart disease should exercise care in using these drags. Some drugs — those known as cyclopropane or halogenated hydrocarbon anesthetics, which are used to anesthetize patients before surgery—increase the effect of adrenergic agonists on both blood pressure and the heart. Internal cranial bleeding (bleeding inside the head) or abnormal heart rhythm may also occur. Adrenergic agonists are also capable of aggravating diabetes in some patients.

The drugs used in treating allergic disorders are categorized broadly as antihistamines, decongestants, bronchodilators, bischromones, ex­pectorants, or corticosteroids. Another category —immunosuppres­sives—which inhibit the immune system, have been tested but are not yet recommended for use. This chapter will review some of the medi­cations commonly used to relieve allergic disorders.

All of the following drugs dilate the air passages (the bronchi and bronchioles) of the lungs as well as affecting, in numerous ways, the blood vessels, heart, small intestines, central nervous system, and, in women, the uterus: epinephrine aqueous suspension (Asmolin and Sus-Phrine); epinephrine hydrochloride (Adrenalin Chloride in a 1:1,000 solution for subcutaneous or intra­muscular injection; available in 1:100 solution for oral inhalation under many trade names); ephedrine (Ephedrine USP); and ethyl-norepinephrine (Bronkephrine). Epinephrine hydrochloride is often the first drug used in treating allergic or allergylike reactions involv­ing multiple organs. Ephedrine is available for both injection and oral use, but most often it is used orally in one of many fixed-ratio combi­nations of drugs. Methoxyphenamine, which is similar to ephedrine, is taken orally. Isoproterenol (available under many trade names) and protokylol (Ventaire) both dilate the air passages of the lungs and affect the blood vessels, heart, small intestines, and, in women, the uterus. Iso­proterenol is available for oral inhalation, as a lozenge to be placed under the tongue, and as a 1:5,000 solution for subcutaneous injec­tion. Protokylol is taken orally. Metaproterenol (Alupent and Metaprel), terbutaline (Brethine and Bricanyl), and salbutamol (Albuterol and Proven til) are rela­tively selective in dilating the airways of the lung and affecting the blood vessels and the uterus. Metaproterenol has been licensed for use orally or by inhalation. Terbutaline is now available as both an oral and an injectable preparation, and it may soon appear in inhala tion form. Salbutamol is available in Europe and some other areas in metered-dose nebulizers for inhalation, but it has not been licensed in the United States.

Irritation of the stomach or intestines, the most common side effects of methylxanthines, can lead to nausea and some­times to abdominal cramping. Headache and vomiting are associated with excessive doses. Because these drugs stimulate secretion of stom­ach acid, patients with ulcers of the stomach or intestines should be cautious about using them. Methylxanthines can also affect muscles, which prevent the contents of the stomach from returning to the esophagus through a valvelike mechanism known as the gastroesoph­ageal sphincter, or the cardiac sphincter. Relaxation of this sphincter permits material to flow backward from the stomach into the esoph­agus. The use of aminophylline in the form of rectal suppositories re­sults in unpredictable aminophylline blood levels; consequently, their effect in treatment becomes unpredictable. The prolonged use of suppositories can even cause rectal irritation and bleeding. If symp­toms of central nervous system stimulation- —such as irritability, rest­lessness, or insomnia—occur, the dose should be reduced. Muscle tremor, or shakiness, may also occur. Overdosage can cause nervous agitation, heightened reflexes, fever, vomiting of blood, convulsions, abnormal heart rhythm, and even death.

The anticholinergic drugs that have been used ex­perimentally are atropine sulfate and ipratropium bromide (SCH-1000). Both are taken by inhalation. Side Effects and Precautions

The methylxanthines class includes dyphylline (known under various trade names); oxtriphylline (Choledyl); theophylline (known under numerous trade names); and theophyl­line ethylenediamine or Aminophyllin and aminophylline. Except for dyphylline, all are converted in the body to theophylline.

Antihistamines are used in treating various disorders of the stom­ach and intestines (the gastrointestinal tract) and of the nose and skin. They are particularly effective in the treatment of hay fever (allergic rhinitis) and other inflammations of the nose (vasomotor rhinitis and intrinsic rhinitis); of hives (urticaria); contact derma­titis; eczema; allergic rashes similar to measles; and allergic reactions in the stomach and intestines (gastrointestinal allergy). The itching associated with rashes such as eczema and contact dermatitis is de­creased, although the appearance of the rash often is not immediately altered. Antihistamines are also used to supplement the treatment of allergic reactions or reactions similar to those of allergies which in­volve more than one body system (for example, the lungs and the skin). These reactions are known medically as systemic allergic reac­tions or idiosyncratic reactions (reactions similar to systemic allergic reactions, but in which allergic mechanisms cannot be demonstrated). In general, antihistamines are not effective in treating asthma, al­though some asthma patients may benefit from treatment with these drugs. Representative Drugs The antihistamines used to treat allergic disorders are commonly divided into six classes, with the following chemical names: ethanola-mine, ethylenediamine, alkylamine, piperazine, and phenothiazine. The sixth class is a group of miscellaneous compounds. Drugs classi­fied as members of the first five classes are chemically related; those in class VI are not necessarily related chemically to each other, nor to members of the five other classes. The drugs in classes I through V have therapeutic properties similar to those of other drugs in the same class. Although patients vary in their responses to specific drugs, their reactions to various chemically related preparations are similar. Sometimes a patient develops a tolerance to an antihistamine drug, which renders the antihistamine ineffective for that patient. This phenomenon is usually dealt with by switching to a chemically un­related antihistamine, or by discontinuing an antihistamine for awhile, which removes the tolerance for that antihistamine. Class I antihistamines —the ethanolamines—are the most potent antihistamines in terms of therapeutic equivalents. This group in­cludes: bromodiphenhydramine; dimenhydrinate (Dramamine and Ambodryl); carbinoxamine (Clistin and Clistin R.A.); clemastine (Tavist); diphenhydramine (Baramine, Benadryl, and SK-Diphenhy-dyramine); diphenylpyraline (Diafen and Hispril); and doxylamine (Decapryn). Class II, the ethylenediamines, includes: methapyrilene (Histadyl) ; pyrilamine (Histalon, Neo-Antergan, Neo-Pyramine, and Nisaval); and tripelennamine (Pyribenzamine, Pbz, and Pbz-SR). Class III, the alkylamines, contains probably the most commonly prescribed antihistamines. Representative compounds are: bromphe­niramine (Dimetane and Dimetane Extentabs); chlorpheniramine (sold under numerous trade names); dexbrompheniramine (Disomer Chronotabs) ; dexchlorpheniramine (Polaramine and Polaramine Repetabs); dimethindine (Forhistal, Forhistal Lontabs, Triten, and Triten Tab-In); and triprolidine (Actidil). Some ethylenediamines and alkylamines are available without pre­scription. They are also available in many nonprescription, fixed-dose combinations marketed as compounds for the relief of colds, hay fever, and headaches. Class IV consists of piperazines and includes cyclizine (Marezine) and meclizine (Bonine). Drugs in this group, along with dimenhydri­nate in class I, are used primarily for treating motion sickness. Phenothiazines make up class V. Representative drugs are methdi-
lazine (Tacaryl), promethazine (Phenergan), and trimeprazine (Temaril). Phenothiazines are used principally as tranquilizers, al­though they also have antihistaminic properties, which make them useful in relieving rashes. Class VI, a group of miscellaneous compounds, includes the chem­ically related azatadine (Optimine) and cyproheptadine (Periactin). Both compounds inhibit the neurotransmitter serotonin, as well as histamine, and are used mostly to alleviate the itching common in skin disorders. Cyproheptadine may be helpful in treating hives caused by exposure to low temperatures (cold urticaria). The hydroxyzines (Atarax and Vistaril) are related most closely to the piperazines. Hydroxyzine, used primarily for treating allergic rashes, has recently been demonstrated as beneficial in the relief of hay fever in some patients; it is also useful as a tranquilizer. Many fixed-ratio combinations of two or more antihistamines, or of antihistamines plus decongestants, are widely used. Another group of antihistamines, the H2 antihistamines, have vastly different treatment properties. Cimetidine (known by the trade name Tagamet) is, however, the only member of this group approved by the Food and Drug Administration, having been approved for treating peptic ulcers but not allergic disorders. Some studies indicate that a combination of cimetidine and an antihistamine from one of the other groups may be more effective than other antihistamines alone in treating some cases of hives that last more than three months (chronic urticaria). Theoretically, cimetidine should not be used alone in the treatment of allergic disorders.

Side effects are rarely serious among the drugs in groups I through VI when they are used in therapeutic doses; side effects that do occur disappear with prolonged use. Sometimes, though, a drug must be discontinued or the dosage reduced. Reactions to these drugs vary markedly, but most patients do not experience bothersome side ef­fects. The most common side effect is drowsiness, especially when phenothiazines and ethanolamines are used. Ethylenediamines usually have a moderately sedative effect, whereas alkylamines generally have the least sedative effect. Abdominal symptoms are the next most common side effect. They include upper abdominal discomfort, nausea, vomiting, loss of appe­tite, and constipation or diarrhea. Relief from some of these effects may be obtained by taking the drug with meals. These effects occur most often when ethylenediamines are used, and least often when ethanolamines or alkylamines are used. Other side effects are a dry mouth and throat, frequent and/or painful urination, awareness of rapid heartbeat, headache, low blood pressure (hypotension), and tightness of the chest. Restlessness, ner­vousness, inability to sleep, and other manifestations of stimulation of the central nervous system occur occasionally, most often when alkyl­amines are used. Symptoms of anxiety —such as heavy, tingling, or weak hands—may also appear. Stimulation of the central nervous system is a striking feature in antihistamine poisoning, symptoms of which may be excitement, hallucinations, lack of coordination, and convulsions. Rare side effects are difficulty urinating, impotence, aller­gic rashes, and aggravation of already existing high blood pressure. Reduction of the blood cell count, an extremely rare complication, is reversible. Other side effects of phenothiazines are jaundice resulting from obstructions in the biliary tract, blood abnormalities, sunlight-sensi­tivity rashes, tremors, and impairment of the central nervous system’s control of posture and movement. Antihistamines can enhance the effects of alcohol and of tranquil­izers, barbiturates, and other sedatives. They should not be used with "mood elevators" (antidepressant drugs) of the monoamine oxi­dase (MAO) inhibitor type. Some antihistamines counter the effects of such drugs as guanethidine, used to treat high blood pressure. Piperazines should not be used during pregnancy. Cyproheptadine should not be given to premature or newborn infants. It has also been reported to cause weight gain. The most common adverse effects of cimetidine are diarrhea, diz­ziness, muscle pain, and rash. Confusion and symptoms of central nervous system disorders have occurred in elderly patients whose kidneys were not functioning properly. These effects, usually asso­ciated with excessive doses, disappeared after the patients stopped taking the drug. In some tests, abnormal liver function (serum transaminase and, rarely, alkaline phosphatase) has been reported. A small increase in the serum creatinine level may occur without other evidence of kidney dysfunction, and a rare form of drug-induced kidney disease known as interstitial nephritis has been observed. These abnormalities, how­ever, have been removed by discontinuing the drug. Enlarged breasts (gynecomastia) in men, as well as swollen and tender nipples, have been noted, but with no evidence of endocrine dysfunction. Some men who have used the drug more than two months have experienced a decreased sperm count. No causal rela- tionship has been established among other adverse effects reported, including a reduced peripheral white blood cell count, inhibition of delayed immune responses after six weeks of treatment, fever, and slow heart rate (bradycardia). Since the main route of excretion of cimetidine is through the kid­neys, the dose must be reduced in patients suffering from impaired kidney function. Cimetidine increases the activity of "blood thinners," warfarinlike anticoagulants commonly prescribed to inhibit blood clotting. Because the drug crosses the placenta, its safety during preg­nancy is questionable.

Uses Decongestants are used primarily in the treatment of hay fever, vasomotor rhinitis, and intrinsic rhinitis. They also provide some relief of allergy of the stomach and intestines (gastrointestinal allergy) and occasionally of hives. For treating hives, however, drugs such as epinephrine and ephedrine are used more widely. Representative Drugs Pseudoephedrine hydrochloride (D-Feda, Novafed, and Sudafed) are probably the most widely used oral decongestants. Others are ephedrine, phenylephrine, phenylpropanolamine (Propadrine), and pseudoephedrine sulfate (Afrinol). Ephedrine, which stimulates the central nervous system more than do such drugs as pseudoephedrine, is used primarily as a bronchodilator. Pseudoephedrine has fewer side effects than ephedrine. Although it is active as a bronchodilator, it is less effective than other drugs in treating asthma. Commonly used intranasal preparations are naphazoline (Privine), oxymetazoline (Afrin), phenylephrine (Neo-Synephrine), tetrahydrozoline (Ty-zine), and zymetazoline (Otrivin). Side Ettects and Precautions Among the side effects of oral preparations, as well as the effects of overdoses of intranasal preparations, are nervousness, dizziness, nausea, awareness of heartbeat (usually rapid), and occasionally stimulation of the central nervous system. Other effects, which usually occur among children, are high blood pressure, slow heart rate, ir regular heart rhythm, and low blood pressure. Children have also been known to experience severe side effects, including sweating, drowsiness, deep sleep, coma, hypotension, and slow heart rate. Be­cause of the effects listed above, caution should be exercised when these drugs are used in people with heart disease, high blood pressure, sugar diabetes, thyroid disease, or any combination of these diseases, or those taking drugs (also known as "mood elevators") of the tri­cyclic class. Patients taking the monoamine oxidase (MAO) inhibitor class of antidepressive drugs should not also use decongestant drugs. Intranasal agents require additional precautions. For example, they should be used only in treating illnesses that are short and relatively severe, that is, illnesses that do not exceed five days in duration. Pro­longed use often causes a "rebound" phenomenon in which, while more and more of the drug is required, the desired effect of the drug becomes increasingly less. More frequent and larger doses of a drug are used, accompanied by the twin risks of overdose and toxicity. Prolonged use causes rhinitis medicamentosum, a condition in which the mucous membranes of the nasal passages become red, boggy, or pale gray and edematous (swelling with fluid between the cells) and in which the inflamed membranes are indistinguishable from other forms of chronic inflammation of the nose, such as year-round hay fever (perennial allergic rhinitis). Topical nasal decongestant solu­tions quickly become contaminated with bacteria and fungi after use, and for this reason, may be sources of infection. Some rules to follow in using spray decongestants are: 1. Rinse the spray tip or dropper in hot water after each use. 2. Do not place the spray tip or dropper inside the nose. 3. Confine use of a particular applicator to one person. 4. Discard the medication and its container when the medica­tion is no longer needed. Something over which people have no control, but which they should be aware of, is that most topical nasal decongestant solutions inter­act with aluminum and thus should not be stored in containers made wholly or in part of the metal. Bronchodilators Uses Bronchodilators are used primarily in treating asthma, but they are also used to treat chronic bronchitis and emphysema, diseases of the lung which chronically obstruct the air passages, as well as to treat bronchiectasis, in which dilatations occur in the air passages of the lungs. Some bronchodilators are useful in alleviating several forms of hives. Epinephrine was the first drug chosen for treating allergic or allergylike responses involving more than one body system, for exam­ple, the simultaneous occurrence of hives and asthma. Another bron-chodilator is aminophylline, which is useful as a supplemental treat­ment in some cases of systemic reaction. Representative Drugs Three classes of bronchodilators are currently being used: adre­nergic agonists (also known as sympathomimetic drugs); methylxan-thines; and anticholinergics (also known as parasympatholytic drugs). Anticholinergic drugs are now being tested and have not yet been ap­proved by the Food and Drug Administration. Other drugs now being tested are alpha adrenergic agonists and prostaglandins.