PRINCIPLES OF PHARMACOLOGY AND MEDICAL THERAPY

Although great strides have been made in surgical technology, some practitioners have overemphasized the role of regional surgical specialists. It is common during residency to focus on operative procedures, but on entering private practice, the fledgling otolaryngologist sometimes is surprised by the need to master previously neglected modes of medical therapy and by the infrequent summons to exercise surgical skills honed in residency. As the 1980s were marked by surgical advances, the 1990s emphasized recognition and medical management of disorders of the ear, nose, throat, head, and neck. Even greater progress is anticipated in the new millennium. This chapter offers general information and philosophical advice to enable clinicians to choose and administer pharmacotherapy effectively for conditions in which medical therapy is appropriate (Fig. 4.1).
DISEASES AND ASSOCIATED CONDITIONS
It is important to establish a specific diagnosis before treating. If therapy is to do more than relieve symptoms, the underlying cause of the problem must be identified and controlled specifically. An exact diagnosis is necessary because some pharmacotherapeutic agents are specific in action. For example, cromolyn is effective for managing immunoglobulin E–mediated allergic rhinitis but is ineffective in managing vasomotor rhinitis and polyp disease. An exact diagnosis also is important because the presence of unrecognized, complicating factors can diminish or negate the effectiveness of therapy. For example, nasal decongestant sprays can cause complicating rhinitis medicamentosa. A corollary to this rule is that if treatment must be administered without a specific diagnosis, the therapeutic response to the medication may render a clue to the proper diagnosis. Not all patients with infection need a culture and sensitivity study, but the response or lack thereof to the antibiotic empirically chosen is useful information for further treatment of the patient.
Establishing an accurate diagnosis on which to base treatment means there rarely is justification for “shotgun therapy,” that is, using enough drugs in the regimen to “hit everything.” An unfortunate example is the practice of some physicians who treat patients with nasal problems with an antibiotic for infection, an antihistamine for allergy, a decongestant for congestion, and a nasal steroid for nonspecific antiinflammatory effect. Such polypharmacy is expensive, is wasteful of medical resources, exposes patients to unneeded medications, to which allergies may develop or which may encourage bacterial resistance, and is entirely inappropriate.
The coexistence of medical conditions other than the one for which the patient is being treated affects the treatment chosen. Physicians must be aware of the medical status of patients and their current medications. For example, patients with diabetes mellitus may need more prolonged antibiotic therapy for an infection than may patients without diabetes. Patients with labile hypertension may respond to systemic decongestants with additional elevations of blood pressure. Patients taking tricyclic antidepressants or monoamine oxidase inhibitors may display a greater vasopressor response to such decongestants because of potentiation by these compounds.
DRUGS OF CHOICE
Dr. Hueston King first acquainted me with the adage, “To one who is good with a hammer, most things resemble a nail.” The proliferation of pharmacologic agents is difficult to follow, and physicians often develop a routine treatment of patients who have a certain set of signs and symptoms. New medications may have no benefit over existing ones, but wise practitioners should be familiar with the standard medications for managing common otolaryngeal disorders and be receptive to new agents as they are made available. This means that the physician’s armamentarium is constantly changing on the basis of reliable new information.
Characteristics and Actions of Drugs
A classic example of the difficulty in discerning the correct drug is in the choice of antibiotics. In no other form of pharmacotherapy has such a continuing explosion of available preparations occurred. By classifying drugs as members of a particular class, such as penicillins, macrolides, cephalosporins (first-, second-, third-, and fourth-generation), and quinolones, and becoming familiar with the general characteristics of the class, physicians can discern more easily the advantages and disadvantages of new preparations as they appear. Even more important is the problem of drug resistance and the mechanism by which this occurs for various antibiotics. This situation is constantly evolving. Physicians need to examine new data as they become available and must remain familiar with the incidence and patterns of antibiotic resistance in their particular geographic areas.
Cost-Benefit Considerations
Even in these days of managed care, with drugs often available to patients for only a nominal copayment, fiscal and social responsibility necessitates that physicians consider drug cost. On the other hand, the most expensive antibiotic is the one that does not work, and the physician’s experience and knowledge of community pathogen patterns of drug sensitivity can be helpful, as can the judicious use of cultures when previous therapy has failed. Table 4.1 lists the cost of antibiotics commonly used in otolaryngology.
The least expensive antibacterial agents are those that can be obtained as generic preparations, although unfortunately marked drug resistance can develop by the time these antibiotics become available in generic form. Parenteral antibiotics are much more expensive than those administered orally, and are rarely indicated in an outpatient setting. An obvious exception is the prescription of intravenous vancomycin for culture-proven methicillin-resistant staphylococci.
Responsible Antibiotic Selection
The increasing prevalence of antibiotic-resistant bacteria (Fig. 4.2, Fig. 4.3) is leading to new approaches in managing common respiratory infections in the outpatient setting (1). Failure of empiric therapy may necessitate culture of, for example, a specimen obtained from the middle meatus, to direct further antibiotic selection. Indiscriminate prescription of broad-spectrum antibiotics for trivial indications undoubtedly promotes the development of drug-resistant bacteria. Infectious disease experts recommend initial use of agents based on community experience and switching from broad- to narrow-spectrum drugs as soon as microbiologic confirmation allows (2).

The multiple factors involved in the choice of an antibacterial drug are summarized in Fig. 4.4. Further complicating decision making is the variety of mechanisms by which therapeutic effectiveness is assessed in vitro, such as area under the concentration-time curve and minimum inhibitory concentration (Fig. 4.5). To most physicians, these are unfamiliar terms, rarely mentioned during residency. Nevertheless, the practitioner must become familiar with these terms and apply them to particular antibiotics as they are introduced to decide whether the new drug offers any advantage over existing preparations. Physicians should avoid practices that hasten development of drug resistance, such as prescribing antibiotics for trivial indications, underdosing or administration for an inadequate length of time, and allowing periods of insufficient drug concentration.
ADMINISTRATION AND DURATION OF THERAPY
Administration and duration of therapy depend on the condition for which the patient is being treated. In general, parenteral therapy is used only if the manner of drug administration or the severity of illness makes oral therapy impractical or ineffective. For conditions such as otitis externa and rhinitis, some preparations are better administered topically than they are systemically. For example, corticosteroids administered intranasally rather than systemically are less likely to cause serious side effects, and the effect is concentrated in the desired area.
Duration of therapy varies with the condition for which the patient is being treated, but the usual tendency is to prescribe antibiotics for too short a period, often leading to recurrence or failure of full resolution of the infection. Many antibiotics now have specific time-length recommendations for specific diseases, such as acute sinusitis or chronic bronchitis. Other therapies administered for chronic disorders, such as steroid nasal sprays for chronic allergic rhinitis, must be monitored to prevent the patient from making them a lifelong habit with the attendant potential side effects and complications. In all instances, the physician must observe the patient and use response to therapy as a guide to duration of treatment.
SIDE EFFECTS AND INTERACTIONS
Information gained during drug development (Table 4.2) and contained in sources such as the Physician’s Desk Reference, USP Drug Information for the Health Care Professional, and package inserts alerts physicians about side effects and drug interactions. This information base grows as rapidly as the list of new drugs. For this reason, many physicians are turning to commercially available products, available in hard copy or computer format, that serve as guides to drug interactions and adverse effects. One such source is Drug Interactions, available from the U.S. Pharmacopoeia.
Numerous drug interactions have been determined. Failure to be aware of these interactions has severe consequences. Monoamine oxidase inhibitors and tricyclic antidepressants potentiate the effect of direct- and indirect-acting adrenergic agents. With monoamine oxidase inhibitors, this potentiation can be seen for as long as 14 days after the compounds are discontinued. Therefore, a-adrenergic agents should be used with caution and in lower doses than usual to treat patients taking either of these preparations. b-Blocking agents are commonly prescribed. Patients taking these preparations are more prone to anaphylactic reactions, as from medications, bee stings, and allergy immunotherapy, than the general population. The reactions often are refractory to conventional therapeutic measures such as injection of epinephrine.
An interaction often not appreciated is that of some antibiotics with oral contraceptives. Many drugs, including some macrolide antibiotics, tetracyclines, metronidazole, penicillins, and trimethoprim-sulfamethoxazole can decrease the effectiveness of oral contraceptives. The patient should be informed of her increased risk of pregnancy and advised to use other methods of contraception for at least one menstrual cycle beyond cessation of such antibiotic therapy (3).
Potentially life-threatening cardiac arrhythmias associated with prolongation of the QT interval have followed administration of the antihistamines terfenadine or astemizole with other drugs metabolized by the cytochrome P-450 enzyme system. Although both these drugs are now off the U.S. market, the fact that this interaction did not come to light for several years after the introduction of these preparations should signal caution to every physician. This problem emphasizes the importance of reporting adverse drug reactions when they occur. Reporting agencies such as the U.S. Pharmacopoeia monitor these reports and issue warnings when appropriate.
RISK OF TERATOGENIC EFFECTS
In prescribing for every female patient from menarche to menopause, it is prudent to ask about the last normal menstrual period to avoid prescribing a preparation that may harm an early pregnancy. As a practical matter, drug-induced fetal abnormalities are fairly rare. When they do occur, however, they represent a catastrophic event. In the general population, the incidence of serious major fetal malformation is 2% to 3%. This percentage encompasses defects incompatible with life, such as anencephaly, or those necessitating extensive surgical correction, such as cleft palate or cardiac defects. If the definition of malformation is broadened to include minor malformations, such as supernumerary digits, the rate approaches 7% to 10% of all births, drug exposure accounting for 2% to 3% of this group. Although the incidence of drug-related birth defects is low, we must strive to keep that percentage as close to zero as possible. As Neibyl (4) stated, “Humans are not rats.” Although almost all research involving the effects of drugs on a developing fetus is conducted with laboratory animals, the length of pregnancy and the time of development of various fetal parts differ radically between humans and rats. Nevertheless, the U.S. Food and Drug Administration has adopted labeling categories for drug use in pregnancy based on human and animal experience (Table 4.3). In general, pregnant patients should be treated with preparations that have the best record of safety. Consultation with the obstetrician may be necessary.
The so-called teratogenic period in human pregnancy spans the time from approximately 31 days after the last menstrual period through the tenth week after the last period. In other words, at about the time of the first missed period and for the next 6 weeks or more, drugs administered to a pregnant woman, who may not realize that her menstrual irregularity signals pregnancy, may affect vital areas of fetal development. The brain continues to develop until birth, and drugs given throughout pregnancy may affect it.
Antihistamines
Most antihistamines are not considered teratogenic. The best-controlled study with human subjects involved chlorpheniramine. This drug was shown not to increase the risk of birth defects in a series of more than 1,000 exposures in the first trimester. Triprolidine also was shown to be safe in a smaller series. A study involving 65 exposures to brompheniramine in the first trimester showed a threefold increase in the relative risk of birth defects associated with this common antihistamine, which is available by prescription and in over-the-counter preparations. Safety for use during pregnancy of the newer nonsedating antihistamines remains a subject of conjecture, although preliminary studies of administration of cetirizine and loratadine to animals are reassuring (5).
Decongestants
Epinephrine and phenylpropanolamine are associated with a substantial increase in risk of birth defects if administered during the first trimester, but pseudoephedrine has not shown any teratogenicity. Topical nasal decongestants are safer in that they have less severe systemic effects, but the risk of habituation and rebound rhinitis during pregnancy is higher than during the nonpregnant state.
Expectorants
Expectorant preparations containing iodides should be avoided because of the potential effect on fetal thyroid function, but guaifenesin is a safe and effective expectorant with no demonstrated teratogenicity. Some over-the-counter cough syrups contain large amounts of alcohol, as much as 25%. Repetitive consumption of these preparations, especially in amounts higher than the recommended doses, can have serious effects on both mother and fetus.
Analgesics
No clear answers have been obtained from the few studies of the use of analgesics during pregnancy. Aspirin is not recommended. It can reduce clotting capability, and its antiprostaglandin effect may decrease the effectiveness of uterine contractions. To a lesser extent, the same can be said of the numerous nonsteroidal antiinflammatory agents. Codeine has little teratogenic risk. In addition to the side effect of constipation, compounding a problem that often exists in pregnancy, there is risk of addiction.
Propoxyphene is probably the analgesic of choice for moderate to severe pain during pregnancy. In a prospective study, 686 first-trimester exposures to propoxyphene were associated with a 4.5% incidence of fetal malformation, a figure indicating that the teratogenic potential of propoxyphene is not great. Because the addiction risk of this drug has been established, including rare instances of neonatal withdrawal symptoms among infants of addicted mothers, propoxyphene should not be used for trivial indications.
Antibiotics
No teratogenicity has been demonstrated for the antibiotics commonly used in the management of otolaryngeal infections; however, some special factors deserve mention. During pregnancy, as a result of increased renal clearance and maternal blood volume, serum levels of amoxicillin and cephalosporins after administration are lower than those achieved in the nonpregnant state. Erythromycin apparently is not teratogenic. Its absorption and passage across the placenta are unpredictable. Except for reversible hepatic dysfunction associated with the estolate form, no serious undesirable side effects of the drug preclude its use in pregnancy.
Sulfonamides apparently have no deleterious effects on the fetus, but in the blood of neonates, they compete with bilirubin for binding sites on albumin, raising the level of free bilirubin in the serum and increasing the risk of kernicterus. Although long-acting sulfonamides and trimethoprim combined with sulfamethoxazole have caused congenital anomalies in animals, controlled trials with humans have not shown any teratogenic risk associated with these compounds. Tetracycline administered during pregnancy can retard skeletal growth and produce discoloration of the deciduous teeth. Clindamycin apparently presents no potential danger to the fetus.
CONCLUSION
Although the available modalities for medical management of problems encountered in otolaryngology are continually expanding and improving, the principles of application remain relatively constant. After the diagnosis is established, the drug most specific for the management of the disorder should be chosen. Factors such as cost-benefit ratio should be considered in the decision. The route and duration of administration must be individualized and altered according to the response obtained. The physician must be aware of side effects and the drug interactions possible because of the patient’s general medical status and other medications taken. Pharmacotherapy during pregnancy or to treat women who may become pregnant during therapy necessitates an even broader range of knowledge of the effects of the medication chosen.