Reduction of the central nervous system adverse effects associated with antihistamines in the management of allergic disorders: Strategies and progress

Reduction of the central nervous system adverse effects associated with antihistamines in the management of allergic disorders: Strategies and progress Fran M. Gengo, PharrnD, FCP Buffalo, N.Y. To reduce the risks associated with the treatment of allergic disorders, physicians should understand the benefits and risks of drugs in the antihistamine class. The risk of central nervous system adverse effects associated with antihistamine use is significant with the use of first-generation antihistamines, which show pharmacologic activity in serotonepgic, c~adrenergic, dopaminet~ic, and muscarinic-cholinergic pathways. Adverse effects reported with the use of first-generation antihistamines most often include dlvwsiness, fatigue, and an inability to concentrate," these effects may result in decreased compliance with therapy. The second-generation antihistamines have the plvperty of low lipid solubility, which slows access across the blood-brain barrier. The low sedative profile of these new drugs may also be linked to a more p~vnounced binding to peripheral rather than brain histamine H z-receptors. The use of antihistamines with lower lipid solubility and greater specificity can provide an effective alternative for the relief of allergic symptoms, can improve compliance, and can reduce neurologic side effects. Because of the differences now recognized in the side effects of drugs of this class, an individualized approach to selection of antihistamine therapy is required. (J Allergy Clin Immunol 1996,'98:$319-25.) Key words: Antihistamines, side effects, risk management

The concept of risk management, also known as total quality management or continuous quality improvement, has become increasingly important in today's health-care delivery system. Although the terminology is new and evolving, the principles of risk management have long been applied to pharmacologic interventions used in the treatment of allergic diseases. Quality and risk are significant considerations for allergists and other physicians who treat patients with allergic disorders regularly; they prescribe a wide array of pharmacologic agents, including [3-adrenergic agonists used as bronchodilators; sympathomimetic agents used as decongestants; phosphodiesterase inhibitors such as theophylline; corticosteroids; muscarinic-anticholinergic agents; and antihistamines. Clinicians and scientists have developed systematic strategies for the use of these drugs, enabling patients to enjoy greater pharmacologic efficacy with a lower risk of drug toxicity.

From the Department of Neurology and Pharmacy, Schools of Medicine and Pharmacy, State University of New York at Buffalo, and the Neuropharmacology Division, Dent Neurologic Institute. Reprint requests: Fran M. Gengo, PharmD, FCP, Millard Fillmore Hospital, 3 Gates Cir., Buffalo, NY 14209. Copyright © 1996 by Mosby-Year Book, Inc. 0091-6749/96 $5.00 + 0 U0/77329

Abbreviations used BAC: Blood alcohol concentration CNS: Central nervous system EEG: Electroencephalographic

Risk management can be illustrated by changes in the use of theophylline. Over the past 25 years, with analyses of pharmacokinetic and pharmacodynamic data, clinicians have determined the doses of theophylline needed to achieve plasma concentrations that produce the highest efficacy with the lowest likelihood of toxicity. L,2 Subpopulations of patients and specific clinical circumstances that might influence either the theophylline concentration needed or the dose required to produce these concentrations have also been identified? ,4 Furthermore, drug-drug interactions that can cause a precipitous reduction or unexpected increase in theophylline concentration have been well studied and catalogued, s On the basis of these data, unique drug delivery formulations have been developed to reduce further the risk of toxicity and to enhance efficacy by producing a more ideal drug concentration-time profile, 6 thereby greatly decreasing the risks associated with the use of theophylline. Although the research and $319

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Blockadeof histamine H1 receptors

Blockadeof ~ -adrenergic receptors

Sedation Drowsiness Weight gain Hypotension

Posmral hypotension Dizziness Reflex tachycardia

clinical procedures that led to these advances were not performed under the rubric of "risk management," they have resulted in achievement of the desired goal. Considerable research focus has been directed toward the risks associated with the use of antihistamines in the management of allergic disorders and the strategies for reducing these risks. Antihistamines produce a variety of pharmacologic and clinical effects. Many of the effects of antihistamines are specialized: effects on the central nervous system (CN8), 7 potential myocardial conduction-related arrhythmia, s and the recently described possibility of tumor growth facilitation by some antihistamines. 9 Optimal therapy with antihistamines requires an understanding of the pharmacologic mechanisms by which antihistamines produce CNS effects, the scope of associated clinical effects, and the problems consequent to these effects. There are successful strategies to manage and reduce the CNS risks associated with antihistamine use. NEUROPHARMACOLOGIC C H A R A C T E R I S T I C S OF A N T I H I S T A M I N E S

Antihistamines have been used for almost 50 years in the management of allergic disorders. At the time of the introduction of pyrilamine in 1944, the action of histamine as a mediator in the immune response was just beginning to be understood. Although histamine meets all of the traditional criteria to be classified as a neurotransmitter, its role as a neurotransmitter was only appreciated in the early to mid-1980s and still remains incompletely understood. Histamine is synthesized within the CNS and exists within synaptic vesicles in presynaptic nerve endings; neuronal tracts use histamine-specific postsynaptic receptors. All three classes of histamine receptors (H 1, H2, and H3) have been identified within the CNS. 1°, ~1 Histaminergic pathways are most dense in some of the midbrain areas, with projections into the cortex and neocortex. It appears that histaminergic pathways may not handle discrete information; instead, they may serve an alerting function, integrating the overall excitability of the telencephalon through a system parallel to or in relay with the reticular activating system. Consequently,

drugs that act as antagonists and block histamine activity in the CNS would decrease the level of arousal or alertness.12, 13 Whereas these compounds act as antagonists at histaminergic receptors, the pharmacologic actions of many antihistamines extend to other important neurotransmitter receptors, often with potency comparable to that exerted at histamine receptors. This characteristic is particularly true of the first-generation, classic antihistamines. In addition to their potent activity in histaminergic pathways, drugs such as diphenhydramine also demonstrate a significant degree of pharmacologic activity in serotonergic, c~-adrenergic, dopaminergic, and muscarinic-cholinergic pathways. Some of the cognitive impairment associated with diphenhydramine may be due in part to c~-adrenergic blockade, as is seen with the administration of clonidine. Similarly, the memory dysfunction that can follow administration of an antihistamine with significant anticholinergic effects can be produced after the administration of pure antimuscarinic agents such as scopolamine. In fact, anticholinergic drug administration has been explored as a model of dementia of the Alzheimer type. It is noteworthy that elderly persons and those with early signs of dementia are particularly sensitive to the cognitive impairment that drugs with antimuscarinic effects can produce. 14, 15 CLINICAL EFFECTS AND CONSEQUENCES OF N E U R O L O G I C A C T I O N S OF ANTIHISTAMINES

When the scope of potential risks associated with antihistamines is considered, the effects of histaminereceptor blockade, a-adrenergic-receptor blockade, and cholinergic-receptor blockade should be evaluated. Common adverse clinical effects of blockade of these pathways (Table I) must be factored into the decision to use an antihistamine. Other factors affecting prescribing decisions are the frequency with which these effects occur and whether the effects limit the utility of these drugs in a significant number of patients. Responses to a 1990 Gallup survey indicated that >50% of patients who take antihistamines would prefer to have their allergy symptoms rather than endure the side effects of their medication. The most common treatment-limiting adverse effects that were reported were drowsiness, fatigue, and an inability to concentrate. One reasonable inference that may be drawn from this poll is that among many patients for whom first-generation antihistamines are prescribed, noncompliance is an important consideration. Not only does noncompliance deny the patient the therapeutic effects of these agents, but it exposes them to the risks associated with untreated disease, including the diminished mental performance that has been seen among patients with untreated allergy. ~6 Marshall and Colon 17 recently studied mental performance and symptoms of allergic disease. Patients with untreated allergic disease who were given mental-performance tests during the

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allergy season did not score as well as did nonallergic patients on these tests. However inexpensive the pertablet cost of the first-generation antihistamines, within the context of managed care delivery, the use of drugs with >50% noncompliance/failure rate would invariably seem to produce a greater cost of care (additional physician visits, etc,). The literature is replete with examples of subjective drowsiness and definite impairmen t of mental performance resulting from the use of first-generation antihistamines. 18-2° Data from our study of the antihistamines meclizine and dimenhydrinate (the 8-chlorotheophylline salt of diphenhydramine) demonstrate drug-induced reductions in objective measures of cognitive function. 21 There was a statistically significant difference in performance with meclizine and with dimenhydrinate as compared with placebo. The dilemma, however, has been in the assignment of clinical relevance to these findings. We have tried to show the relevance of these findings in controlled studies comparing these effects with those of blood alcohol concentrations (BAC) on the same measures of mental performance. 2° Fig. 1 shows that the magnitude of the peak effect produced by dimenhydrinate is in the range of that expected with a BAC of about 0.08 gin/100 ml (g%). Although many assumptions are made in this comparison of the effects of ethanol and antihistamines, the approach provides broad insight into whether the magnitude of the difference between antihistamine and placebo is sufficiently large to be of practical concern. A further extension of this comparison is to express the data as the percentage of patients who experience an effect of the antihistamine that would be associated with a BAC of

>0.08 g%. This method avoids some of the problems associated with pooled data and average effect and provides insight into the magnitude of antihistaminic effect and the frequency with which it produces a relevant impairment. Data from the same meclizine and dimenhydrinate study2° reveal that after the administration of dimenhydrinate, approximately 25% of patients exhibited a performance deficit that, had it been produced by alcohol, would have been associated with a BAC of >0.08 g%. The same was true of approximately 15% of patients given meclizine. Similar data after the administration of diphenhydramine 50 mg indicate that almost 40% of subjects experience a BAC effect of >0.08 g%. STRATEGIES TO M I N I M I Z E A N D M A N A G E RISKS The risks associated with the CNS effects produced by antihistamines occur with significant frequency and are of such magnitude that pharmacologic strategies to reduce them have been formulated. Antihistamines, particularly the classic antihistamines, produce these actions in the CNS because of their pharmacologic potency at several important neurotransmitter receptors and their ready accessibility to the brain. One strategy to reduce the CNS effects of these drugs is to limit CNS access by developing agents with active histaminergic antagonist molecules and a low partitioning coefficient into lipids. This type of agent traverses the blood-brain barrier very slowly. The physiologic functions of the blood-brain barrier are complex; it plays a primary role in determining the access of chemicals from the vascular lumina to the neuronal tissue of the brain. 7 The low permeability of the blood-brain barrier results

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from the joining of the endothelial cells of the cerebral capillaries to each other by tight junctions that leave essentially no intercellular space for drugs or chemicals to pass from the lumen of the capillary to neuronal tissue. To reach the brain, therefore, drugs must become soluble in the lipid membrane of the cell and pass through the cell membrane, a slower process in drugs with low lipid solubility. In single-dosing or acute-dosing conditions in which total-body clearance of the drug is more rapid than the rate of drug uptake to the brain, the absolute extent of uptake for drugs with lower lipid solubility will also be limited. This strategy was used in the development of some of the first second-generation antihistamines, such as ter-

fenadine. In studies in human beings in which singledose conditions were used, the uptake of terfenadine into cerebrospinal fluid was consistently low. 22 In animal studies measuring histamine-receptor occupancy, 23 access to neurologic sites of action was more limited with acute administration of newer drugs than with the older, more lipid-soluble antihistamines, resulting in a lower risk of clinical adverse effects. Studies that document the lesser CNS effects of terfenadine range from clinical trial data reporting the frequency of patient complaints of drowsiness 24 to measurements of mental performance 25 and electroencephalographic (EEG) assessments of drug effect. -~6E E G measurements of drivers after singledose administration of terfenadine, chlorpheniramine,

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or placebo showed a clear difference in the neurophysiologic effects of placebo and chlorpheniramine but no significant differences between placebo and terfenadine. These differences also were seen in behavioral end points; the number of errors after administration of chlorpheniramine was greater than with placebo or terfenadine. In measures made several hours after dosing, data show a trend for a difference between placebo and terfenadine that is consistent with the concept that low lipid solubility slows the rate of drug uptake into the CNS rather than producing an absolute effect on the extent of drug equilibration between plasma and brain concentrations. 26 Terfenadine has been joined by other second-generation antihistamines, including loratadine, astemizole, and cetirizine. Although they also have a lower lipid solubility, they may still have significant potency at CNS receptor sites other than at histaminergic receptor sites. If these drugs were to gain significant access to the CNS, they could produce an effect not only at histaminergic receptor sites but also at other receptor sites. Continuous or long-term dosing increases the likelihood of significant brain exposure to these drugs because lower lipid solubility does not decrease the potential of drug uptake into the brain; it simply slows the rate of drug

uptake, z-/ When drug concentrations are maintained during long-term dosing, brain and blood concentrations slowly equilibrate, enabling significant access of relatively water-soluble drugs into the brain. This effect may explain emerging data suggesting that long-term dosing of drugs such as terfenadine produces CNS effects evident after 4 or 5 days. Votkerts et al. 2s tested simulated-driving performance and memory functioning; terfenadine (120 rag/day) produced a clear effect on the fourth day of treatment, impairing memory function not impairing simulated highway driving. The magnitude of these effects is relative; nevertheless, with continuous dosing, drugs with lower lipid solubility gain access to the brain and produce measurable cognitive effects. A second strategy to minimize the CNS effects of antihistamines is to increase their pharmacologic specificity. As seen in Fig. 2, the pharmacologic specificity of hydrovzine is such that its activity at other neurotransmitter-receptor sites is as high as its activity at histaminereceptor sites. 29 In comparison, the pharmacologic specificity of cetirizine, the major metabolite of hydrovzine, is such that its pharmacologic activity is limited to histaminereceptor sites. Cetirizine not only has a lower lipid solubility due to the oxidation of the hydroxy group to a more

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polar carboxylic acid but also is a more precise pharmacologic agent. Thus, whereas it is similar to terfenadine, loratadine, and astemizole in that it is relatively lipid insoluble and crosses the blood-brain barrier slowly, its pharmacologic activity in the CNS is limited to histaminereceptor blockade. Cetirizine is devoid of relevant activity at other neurotransmitter-receptor sites. Clinical trials and pharmacologic studies have shown a lack of significant CNS effects with cetirizine 10 rag. 3° It is unclear whether this property is due to pharmacologic specificity, lipid insolubility, or both. As can be seen in Fig. 3, studies from our laboratory21 have demonstrated that quantitative measurements of drowsiness and mental performance begin at dose s of 20 rag. In acute dosing studies, administration of 5 and 10 mg doses of cetirizine show no differences from placebo. Data from Volkerts et al. 28 demonstrate no difference in driving tests or memory tasks between cetirizine (10 rag/day) and placebo at subchronic doses. In contrast, small but significant CNS effects have been shown after several consecutive days of loratadine~1 and terfenadine2s administration. Slight and limited E E G changes were shown with loratadine (10 and 40 mg) in a clinical pharmacologic study of healthy volunteers by Pechadre et al. 31 Ongoing studies in our laboratory are exploring the effects of several of these second-generation antihistamines after a subchronic dosing schedule in a population of elderly patients with allergic diseases. We will evaluate how age-related changes in the potency of the blood-brain barrier, combined with long-term dosing that enables equilibration between plasma and neuronal tissue, influence the risk-benefit ratio of second-generation antihistamines. In summary, antihistamines are an indispensable class of drugs in the treatment of allergic disease and provide patients with relief from rhinitis, conjunctivitis, urticaria, and acute allergic reactions. Older, first-generation antihistamines are associated with significant CNS risks in 25% to 35% of patients. For these patients the second-generation antihistamines provide equally effective relief of allergic symptoms without relevant CNS effects. Although data regarding the CNS effects of these drugs after long-term dosing and in specific populations are evolving, the CNS effects measured in these particular circumstances appear to be much smaller in magnitude than those produced by the older antihistamines, and of no practical consequence for activities of daily living. REFERENCES

1. Lesko LJ. Dose-dependent kinetics of theophylline. J Allergy Clin Immunol 1986;78:723-7. 2. Jenne JW, Wyze E, Rood FS, McDonald FM. Pharmacokinetics of theophylline: application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther 1972; 13:349-60. 3. Jenne JW. Effect of disease states on theophylline elimination. J Allergy Clin Immunol 1986;78:727-35. 4. Juscko WJ, Gardner MJ, Manglone A, Schentag JJ, Kour JR, Vance JW. Factors affecting theophylline clearance:

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RAA. Does cetirizine belong to the new generation of antihistamines? An investigation into its acute and subchronic effects on highway driving, psychometric testing performance, and daytime sleepiness. Hum Psychopharmacol 1992;7:227-38. 29. Gengo FM, Dabranzo J, Yurchak A, Love S, Miller JK. The relative antihistaminic and psychomotor effect of hydroxyzine and cetirizine. Clin Pharm Ther 1987;42:265-72. 30. Spencer CM, Faulds D, Peters DH. Cetirizine: a reappraisal of its pharmacological properties and therapeutic use in selected allergic disorders. Drugs 1993;46: 1055-80. 31. Pechadre JC, Beudin P, Eschalier A, Trolese JF, Rihoux J-P. A comparison of the central and peripheral effects of cefirizine and loratadine. J Intern Med Res 1991;19:289-95.

Chronic urticaria: Pathophysiology and treatment approaches Michael D. Tharp, MD Chicago, Ill. Ul¢icaHa, a cutaneous reaction pattern, varies clinically and histopathologically. The origin of acute urticaria can be detected in some cases; in patients with chronic urticaria, however, the cause is' rarely identified. Thus, most patients with chronic urticaria are considered to have idiopathic disease. The dermal mast cell and its mediators may play a central role in chronic idiopathic urticaria. Other inflammatory cells, including Iymphocytes and polymorphonuclear cells, have also been implicated. Treatment is based on identification of the inflammatory cells within skin lesions and blockage of the effects of histamine in the skin. Urticaria in which a lymphocyte-predominant infiltrate is seen often responds" to one or more H1 antihistamines. Recently, a new generation of nonsedating or mildly sedating H 1 antihistamines has proved useful in the management of these cases. Antihistamine use alone may be unsuccessful in urticaria in which polymorphonuclear neutrophils predominate; fi'equently, the addition of agents that alter polymolphonuclear neutrophil function, such as colchicine or dapsone, is required. During the inO'oduction of antihistamine and anti-polymotphonuclear neutrophil therapy, a simultaneous brief course of systemic cot~icosteroid therapy may be necessary, but the extended use of systemic corticosteroids should be avoided because of significant adverse effects. As the pathophysiologic mechanisms responsible for chronic urticaria are better defined, more effective therapeutic agents should become available. (J Allergy Clin hnmunol 1996;98:$325-30.) Key words: Urticaria, corticosteroids, H z antihistamines, cetirizine, chronic disease, dJ~g therapy

From the Department of Dermatology, University of Pittsburgh. Reprint requests: Michael D. Tharp, MD, Department of Dermatology, Rush Presbyterian St. Luke's Medical Center, 630 S. Hermitage, 507 Kidston House, Chicago, IL 60612. Copyright © 1996 by Mosby-Year Book, Inc. 0091-6749/96 $5.00 + 0 1/0/68334

The treatment of patients with chronic urticaria, or hives, can present a significant challenge to the most experienced physicians. Urticaria is a common disorder that affects as many as 25% of all people at some time during their lives. 1 It is not a single disease but a cutaneous reaction pattern for which there are multiple potential causes. The clinical expression of this disease varies from patient to patient, as do its duration of