Serum theophylline and phenytoin levels: Can we afford to do them? Can we afford not to?

SPECIAL CONTRIBUTION cost effectiveness, laboratory testing, phenytoin and theophylline levels; phenytoin, testing, indications; theophylline, testing, indications

Serum Theophylline and Phenytoin Levels: Can We Afford To Do Them?

Can We Afford Not To?

Gloria Kuhn, DO, FACEP Detroit, Michigan

From the Department of Emergency Medicine, Mount Carmel Mercy Hospital,

Detroit, Michigan.

Presented at the Winter Symposium Advances Track of the American College of Emergency Physicians in San Diego,

California, April 1985.

Address for reprints: Gloria Kuhn, DO, FACEE Department of Emergency

Medicine, Mount Carmel Mercy Hospital, 6071 Outer Drive, Detroit, Michigan 48235

The following factors must be considered when determining the need for theophylline and diphenylhydantoin (DPH) levels: accuracy and re- producibility, turnaround time, and cost-benefit ratio for the patient. Serum levels must bear a relationship to the therapeutic effects of the drugs. In addition, the pharmacology of the drugs must be of such an order of com- plexity that there is not a simple relationship between dosage and serum levels. [Kuhn G: Serum theophylline and phenytoin levels: Can we afford to do them? Can we afford not to? Ann Emerg Med March 1986;15:344-348.]

I N T R O D U C T I O N Asthma has been called the most prevalent chronic disease of childhood.]

The true incidence is difficult to measure because a number of diseases have a bronchospastic component. The incidence is greatest in young children, decreases in adolescents, and increases again in early adult life. Rates also are high in older individuals, but frequently these patients also are diagnosed as having chronic bronchitis and/or emphysema. 2 For years, theophylline has been used for a number of diseases with a bronchospastic component, so that a strict differential between asthma, chronic bronchitis, and emphysema was not necessary on an emergency basis. The efficacy of theophylline in irre- versible airway obstruction, however, recently has been questioned. 3

The overall incidence of epilepsy is between 0.3% and 0.7% per year. In the United States, 23,000 to 147,000 new cases of epilepsy occur annually. The incidence of both primary and secondary seizures varies between 30 and 50 per 100,000 population. If nonrecurrent seizures and febrile seizures are included, the incidence may double. 4

PHARMACOKINETIC PRINCIPLES A drug's rate of absorption, distribution in the body, half-life, therapeutic

range, and excretion determine clinical drug use. After a drug is absorbed, it is mixed with plasma, may become partially

bound to plasma proteins, and then distributes in variable quantities to the tissues of the body. The volume of distribution depends on how the drug distributes to tissues rather than concentrating in the plasma.

The biologic half-life of the drug is the time it takes to decrease by 50% after absorption and distribution. In most cases, the half-life is independent of dose, concentration, or route of admimstration and is described as first- order kinetics. This process, however, is not true of theophylline or diphenylhydantoin (DPH).

It may be desirable to administer an initial loading dose of drugs with a half-life of more than ten hours so that a therapeutic level can be reached quickly. If this is not done, approximately four biologic half-lives are necessary to achieve a steady-state concentration, s Because both theophyllme and DPH have long biologic half-lives, this principle is used when initiating ther- apy with either drug.

Both theophylline and DPH have nonlinear pharmacokinetics. The most important cause of nonlinearity is the limited capacity of certain drug-metabolizing enzyme systems. As a result, the biologic half-life increases with rising dose or plasma concentrations. Therefore, when the patient is near therapeutic range, a small increase in the amount of drug administered may

170/344 Annals of Emergency Medicine 15:3 March 1986

TABLE 1. Calculating maintenance infusion (based on ideal body weight)

Adult nonsmoker

Adult smoker

Age > 50

Chronic obstructive pulmonary disease

Congestive heart failure

Liver disease

Children < 18

Rosen 4 Emergency Medicine

(mg/kg/h) 0.5

0.9

0.4

0.6 - 0.7

0.35 - 0.68

0.25 - 0.45

1.00

Sahn2O Pulmonary Emergencies

(mg/kg/h) 0.6

0.8

0.4

0.2

result in a disproportionately large increase in the serum level.6, 7

The therapeutic concentration is the range in which a drug is effective but not toxic. The range of both theophylline and phenytoin is from 10 to 20 ~g/kg. Below 10 }xg/kg the drugs are not effective in the majority of patients, and above 20 ~g/kg an increas- ing number of patients begin to man- ifest toxic symptoms.S, 9

Both drugs are metabolized in the liver. A number of factors particularly affect the ability of the liver to metabolize theophylline, affecting its rate of clearance.

PHARMACOLOGY OF THEOPHYLLINE

Theophyl l ine is a d imethylated xanthine similar in structure to caffeine or theobromine. It may be administered orally, rectally, or parenterally and is well absorbed by all routes. Because rectal suppositories result in erratic absorption, the drug must be in solution form if this route is to be used. 'o When theophylline is mixed with ethylenediamine, the pH is raised sufficiently to allow it to become water soluble. It then may be administered parenterally. This compound, called aminophylline, contains approximately 80% theophylline. 1I

The drug is absorbed rapidly and complete ly in the s tomach when given as a liquid or plain tablet. Rate of tablet disintegration and dissolu- tion of the formulation in the stom- ach determine the rate and com- pleteness of absorptionA2 After enter- ing the systemic circulation, approximately 60% of the drug is bound to plasma proteins, and the remaining 40% distributes throughout the body water. Serum concentrations are in

FIGURE. Factors that may vary the metabolism of theophylline.

equilibrium with tissue concentrations of the drag within one hour after IV injection. 7 The volume of distribution is approximately 0.45 L/kg in both children and adultsA 3

Mechanism of Action Because theophylline inhibits phos-

phodiesterase, delayed degradation of intracelluler cyclic adenosine mono- phosphate (cAMP) occurs. This higher concentration of cAMP has been used to explain how theophylline produces bronchodilatation, but the concentrations obtained do not appear to be suf- ficient to produce this effect, 14 nor does this theory explain why other phosphodiesterase inhibitors do not result in bronchodilatation. Other proposed mechanisms include prostaglandin antagonism, is stimulation of cate- cholamine release, 16 beta agonist activity, 17 and adenosine receptor antagonism. 18

The latter explanation is based on the fact that adenosine can induce bronchoconstriction in the asthmatic patient. Theophylline competitively inhibits adenosine receptors in various tissues within the therapeutic range. Whatever its mechanism of action, theophylline has proven to be of value in controlling the symptoms of chronic asthma and acute exacerbations of the disease.

Metabolism and Excretion Theophylline is eliminated from

the body by biotransformation in the liver, with less than 10% of the parent compound being excreted in the urine unchanged. Grygiel and associates have proposed that the enzymes re-

Increases Metabolism Smoking (tobacco, marijuana) Childhood Charcoal-broiled meats Phenobarbital

Decreases Metabolism Liver disease Congestive heart failure Cor pulmonale Chronic obstructive lung

disease Caffeine Cimetidine Erythromycin Propanolol Triacetyloleandomycin

sponsible for inact ivat ion of theophylline include multiple forms of cytochrome P-450A 9 These oxidases are highly sensi t ive to both the enzyme-inhibiting and -stimulating properties of various drugs, environ- mental and chemical factors, disease processes, and patient age. All of these variables may, by act ing on this enzyme system, alter the ability of the individual patient to eliminate the drug.

Patient variability in metabolizing theophylline makes the process of pre- dicting serum values based on dosage extremely difficult. In addition, because of nonlinear pharmacokinetics, in at least some patients small dose increases may cause disproportionate increases in serum concentrations. Factors that vary the metabolism of the drug are shown (Figure).

Because of these factors, maintenance levels may only be estimated and must be verified by serum levels

15:3 March 1986 Annals of Emergency Medicine 345/171

THEOPHYLLINE & PHENYTOIN LEVELS Kuhn

TABLE 2. Side effects of theophylline

Serum Level > 20 mg/mL

> 35 mg/mL

> 35 mg/mL

Symptoms Gastrointestinal: Nausea; vomiting; hematemesis (children);

diarrhea; abdominal pain and cramping CNS: Headache; tremulousness; nervousness; grand mal

seizures Cardiac: Atrial dysrhythmias; ventricular dysrhythmias

TABLE 3. Side effects of DPH

Type Gastrointestinal

Symptoms of nausea and vomiting CNS

Nervousness, hand tremors, ataxia, nystagmus, seizures; involves dysfunction of cerebellar and vestibular system

Hematologic Gingival hyperplasia Dermatologic complications

Cause

Dose related

Dose related Hypersensitivity Hypersensitivity Hypersensitivity

TABLE 4. Plasma concentrations and symptoms of excess levels of DPH

Serum Levels 20 i~g/mL 30 - 40 lu, g/mL 40 #g/mL

Symptoms Nystagmus Ataxia Lethargy, confusion, increased number of seizures

for each patient. The variations in rec- o m m e n d a t i o n s be tween two texts dealing with the question are shown (Table 1). This variability demonstrates that the problem is very complex.

Side Effects and Toxicity Because not all patients exhibit gas-

trointestinal symptoms prior to man- ifestations of cardiac and CNS toxicity, there is no orderly progression of symptoms to warn of impending ma- jor problems of toxicity. The symptoms seen wi th rising serum levels and the levels at which these symptoms usually appear are shown (Table 2).1o

PHARMACOLOGY OF DPH Mechanism of Action

DPH was in t roduced in 1938 by M e r r i t t a n d P u t n a m , w h o h a d screened many compounds in order to

find an agent that is as effective as phenobarbital in the treatment of seizures but that has fewer side effects. DPH in therapeut ic concentra t ions does not exhibit sedative properties. It can limit the development of maximal seizure activity and reduce the spread of the seizure process from an active focus.

DPH has a stabilizing effect on all neuronal membranes. This may result either directly or indirectly from an effect on the movements of ions across cell membranes. DPH decreases rest- ing fluxes of sodium ions as well as sodium currents that flow during action potentials in chemically induced depolarization. Influx of calcium ions during depolar iza t ion is decreased either independent ly or as a conse- quence of reduced intracellular concentrations of sodium. There also is a delay in the ac t iva t ion of ou tward

potass ium current during an act ion potential, leading to an increased re- fractory period and a decrease in repet- itive firing. 21 While the exact intracellular mechanism leading to seizure control has not been ellucidated com- pletely, the drug has proven to be of value in the control of seizure disor- ders for the past 40 years.

Pharmacokinetics, Absorption, Distribution and Excretion

The pharmacokinetics of DPH are based on its l imi ted aqueous sol- ubility, dose-dependent el imination, and hepatic inactivation, which may be inhibited by other drags. DPH is a very weak acid with poor water sol- ubility. The plasma half-life averages 24 hours, but half-lives of as much as 96 hours have been reported. 21 Serum concentrations are not related linearly to daily dose; small dosage increments can result in large increases, especially within the therapeutic range, because of dose-dependent elimination32 Op- timal serum concentrations range between 1O txg/mL and 20 ~xg/mL, with concentrations less than 10 Ixg being ineffective and concentrations above 25 ixg/mL causing toxicity.

Diphenylhydan to in may be given orally or intravenously. Oral absorption is slow and sometimes is variable or incomplete . Peak concentra t ions after a single oral dose may occur as early as two hours or as late as six hours after administration. The drug may be given W, but no faster than 25 mg /min to 50 m g / m i n in order to avoid such undesirable side effects as hypotension and cardiac arrhythmias. The drug is bound extensively (90%) to plasma proteins. Fractional binding in tissues, including the brain, is the same as in plasma, resulting in an ap- parent volume of distribution of about 64% of body weight. Concentration in cerebral spinal fluid is equal to the un- bound fraction in plasma. Two percent of the drug is excreted unchanged in urine; the remainder is metabolized

primarily by the hepatic microsomal enzymes. When the plasma concentration is less than 10 lxg/mL elimination follows linear kinetics, but at higher concentrations dose-dependent kinetics occur with plasma half-life increas- ing. s This may occur because enzyme systems have reached saturation or are inhibited by metabolites. 22

Toxicity When the drug is given too rapidly


W, the most notable toxic effects are card iovascular co l lapse and/or CNS depression. Overdose by the oral route features signs referable pr imar i ly to the c e r e b e l l u m and v e s t i b u l a r systems. Toxic effects after chronic ad- m i n i s t r a t i o n involve bo th the CNS and gastrointestinal systems. The cat- egories of side effects (Table 3) and the p l a s m a c o n c e n t r a t i o n s a s s o c i a t e d wi th various central nervous sys tem side effects (Table 4) are shown.

METHODS OF MEASURING DRUG CONCENTRATIONS

A n u m b e r of methods , inc lud ing high-pressure l iquid chromatography (HPLC) and e n z y m e i m m u n o a s s a y t echn iques (EMIT), are avai lable to measure concentra t ions of theophyl- l ine and DPH. These m e t h o d s are rapid and specific, and require as l i t t le as 0.2 mL of blood. The EMIT method is more rapid than o ther me thods , may be adapted for processing large batches of samples, and may be used to moni tor s emm levels of a number of drugs. 23 In the future, some of these tests will require less than five min- u t e s f rom the t i m e the s amp le is drawn to the t ime the answer is pro- vide&

Although rapid and accurate results are possible, a recent s tudy revealed a 28% error in the reporting of laboratory values in assaying theophyll ine levels. g3 There was no s igni f icant difference in performance between hospital and referral laboratories, nor was there a difference in performance between labora tor ies us ing the EMIT and those using the HPLC method. The authors concluded that error was no t i n h e r e n t in the type of assay method used, but rather occurred due to the handling or performance of the test. Costs of the test ranged from $12 to $25; wi th a mean of $20.

Pa t ien ts w i th acute s y m p t o m s of a s t h m a or se izures are very i l l and have the p o t e n t i a l for severe mor- b idi ty and mor ta l i ty if they are not p rope r ly t rea ted . T h e o p h y l l i n e and DPH, mainstays of t reatment in these d isorders , are drugs w i t h c o m p l e x pharmacologies. Many of the patients seen are already under treatment, and thus may be expected to have some level of the drug already in their system. It is impossible to predict this level based on history. The therapeutic range of each drug is narrow, and frequently there are no warning signs or

s y m p t o m s to hera ld severe toxicity. Part icularly in the case of theophylline, there is no clear relationship between dosage and expected serum levels because a large number of factors affect the m e t a b o l i s m of the drug. When patients are near the therapeutic range, small increments in dosage may result in disproportionately large increases in serum levels because the drug does not always fol low l inear pharmacokinetics.

When we are faced wi th acutely ill patients in the emergency department and do not have informat ion on pa- t ient compliance or individual abil i ty to metabolize these drugs, it is critical to d e t e r m i n e the s e r u m level accurately so that we may optimize ther- apy. A number of available tests allow us to gather this information so that we may give theophyll ine and DPH in a control led and efficacious manner when necessary.

The costs of these tests vary, but they usual ly are under $50. The cost of one hospital day averages $350; one day in an intensive care unit averages $1,000. This does not take into consid- e r a t i on the f inanc ia l cos t s of los t wages or t ime lost at other activities. Clear ly , if h o s p i t a l i z a t i o n can be avoided, a clear cost-benefit ratio is present.

SUMMARY Historically theophyll ine and DPH

have p roven to be ef fec t ive in the t reatment of as thma and seizures. The pharmacology of these medicat ions is complex, wi th a narrow therapeut ic range and s igni f icant s ide effects if s e rum levels are toxic. There is no way to predict serum levels accurately based on history or by calculation of ideal dosages. Available serum assays can predict serum levels rapidly and accurately. These assays are cost effec- t ive in o p t im iz ing the rapy and de- creasing the incidence of toxicity.

REFERENCES 1. Fleisher G, Ludwig S: Textbook of Pedi- atric Emergency Medicine. Baltimore, Williams and Wilkins, 1983, p 532.

2. Dodge RR, Burroughs WS: Prevalence and incidence of asthma and asthma-like symptoms in a general population sam- ple. Am Rev Respir Dis 1982;122:567-575.

3. Alexander MR, Dull WL, Kasik JE: Treatment of COPD with orally administered theophylline, A double blind con-

trolled study. JAMA 1980;244:2286-2290.

4. Rosen P {ed): Emergency Medicine Concepts and Clinical Practice, vol 2. St Louis, CV Mosby Co, 1983.

5. Goth A: Medical Pharmacology. St Louis, CV Mosby Co, 1984, p 14.

6. Bevan J, Thompson J: Essentials of Pharmacology, ed 3. New York, Harper and Row, 1983, pp 46-68.

7. Levy G, Koysoko R: Pharmacokinetic analysis of the effect of aminophylline on pulmonary function in asthmatic children. J Pediatr 1975;86:789-793.

8. Glaser GH, Penry JK, Woodbury DM (eds): Antiepileptic Drugs: Mechanism of Action. New York, Rosen Press, 1980.

9. Weinberger M, Hendeles L, Ahrens R: Clinical pharmacology of drugs used for asthma. Pediatr Clin North Am 1981; 28:1:47-75.

10. Lillehei JP: Aminophylline: Oral ver- sus rectal administration. JAMA 1968; 205:530.

11. Hendeles L, Weinberger M: The- ophylline: A state of the art review. Phar- macotherapy 1983;3:2-44.

12. Weinberger M, Hendeles L, Bighley L: The relation of product formulation to absorption of oral theophylline. N Engl J Med 1978;299:852-857.

13. Gibaldi M, Levy G: Pharmacokinetics in cl inical practice. JAMA 1964;235: 1864-1867.

14. Bergstrand H: Phosphodiesterase inhi- bition and theophylline. Eur J Respir Dis (8uppl 109) 1980;6:37-44.

15. Horrobin DF, Manku WS, Franks DJ, et al: Methylxanthine phosphodiesterase inhibitors behave as prostaglanding antag- onist in a prefused rat mesenteric artery study. Prostaglandin 1977;13:33-40.

16. Higbee MD, Kumar M, Galant SP: D e t e r m i n a t i o n of endogenous cate- cholamine release by theophylline: A proposed additional mechanism of action for theophylline. J Allergy Clin Immunol 1982;70:377-382.

17. Mackay AD, Baldwin CJ, Tattersfield AE: Action of intravenous aminophylline on normal airways. Am Rev Respir Dis 1983;127:609-619.

18. Fredholm BB: Theophylline actions on adenosine receptors. Eur J Respir Dis (Suppl) 1980;109:29-36.

19. Grygiel JJ, Wing LMH, Farkaf J, et al: Effects of allopurinol of metabolism in clearance. Clin Pharmacol Ther 1979;26: 666-667. 20. Sahn S: Pulmonary Emergencies. Toronto, Churchill, Livingston Co, 1982.

21. Goodman A, Gilman L: The Pharma- cology Basis of Therapeutics, ed 6. New

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THEOPHLYLLINE & PHENYTOIN LEVELS Kuhn

York, MacMillan Publishing Co., 1980, pp 448-475.

22. Smith D, Delgado Escueta A, Cramer

J, et al: H i s to r i ca l pe r spec t ive on the choice of antiepileptic drugs for the treat- m e n t of se izures in adults . Neurology {suppl 1) 1983;33:2-5.

23. Bonham A, Hendles L, Vaughn L: The rel iabil i ty of serum theophyl l ine deter- mina t ion from clinical laboratories. A m Rev Respir Dis 1980;122:829-831.


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Serum theophylline and phenytoin levels: Can we afford to do them? Can we afford not to?