Drugs Affecting the Respiratory System - ACS Publications - American

14 Recent Innovations in Theophylline-Like Bronchodilator Drugs

Downloaded by AUBURN UNIV on April 19, 2017 | http://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch014

RICHARD J. SEIDEHAMEL and DAVIS L. TEMPLE, JR. Mead Johnson Pharmaceuticals, Εvansville, IN 47721

Theophylline is recognized as a primary or first-line drug in the treatment of chronic asthma and is especially valuable in moderate-to-severe asthma where maintenance therapy is essential. It is generally more effective than cromolyn in preventing the symptoms of asthma (1) and, when used on a continued basis, is not associated with tolerance or tachyphylaxis. There are other observations which attest to the popularity of this drug. In 1977 some 26 million prescriptions were written for bronchodilators; 11 million of these or 42%, were for theophylline products, and sales for these theophylline products totaled 60 million dollars, up 30% over the previous year. Furthermore, more pharma ceutical houses are getting involved in the theophylline business, and there have been numerous publications con cerning all aspects of theophylline. Theophylline, from the time of its entry into broncho pulmonary medicine in the 1930's (2) has not always been so popular. Clinical results with the drug over the years have been erratic, mainly because of a remarkable patient-to -patient and sometimes within-patient variability in response to generally recommended doses. I t i s now recognized, through the help of pharmacokinetic and metabolic s t u d i e s , that i n d i v i d u a l s can vary g r e a t l y i n t h e i r serum theophyl l i n e l e v e l s f o l l o w i n g a standard o r a l dose of the drug. F i g u r e 1 shows what the c l i n i c i a n might expect when he gives an equal mg/kg o r a l dose. These p a t i e n t s ( i . e . , s i x ) may f a l l i n t o one of four c a t e g o r i e s according to peak-serum t h e o p h y l l i n e l e v e l s . While the m a j o r i t y may f a l l i n t o the 10 to 20 yg/ml or supposedly optimal t h e r a p e u t i c range (3) at a recommended dose l e v e l and r e c e i v e maximal broncho d i l a t o r b e n e f i t s with l i t t l e or no s i d e e f f e c t s , others may f a l l i n t o a higher and t o x i c range and e x h i b i t s i d e e f f e c t s l i k e CNS and c a r d i o v a s c u l a r s t i m u l a t i o n or i n t o the lower and subtherapeutic range and get no b e n e f i t s a t a l l from the drug. T h i s f i g u r e serves to i l l u s t r a t e the narrow optimal

0-8412-0536-l/80/47-118-285$05.00/0 © 1980 American Chemical Society

Temple; Drugs Affecting the Respiratory System ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

286

DRUGS AFFECTING THE RESPIRATORY SYSTEM


PEAK BLOOD LEVELS (ORAL THEOPHYLLINE) 30 TOXIC RANGE

20

10 MINIMAL THERAPEUTIC RANGE SUBTHERAPEUTIC RANGE 0 L Figure 1. Blood levels of theophylline showing the potential interpatient variability following an equal mg/kg oral dose of a theophylline product



14.

SEiDEHAMEL

AND TEMPLE

Theophylline-Like Bronchodilator Drugs

serum t h e o p h y l l i n e range. Yet, there i s s u f f i c i e n t potency s e p a r a t i o n between d e s i r a b l e and u n d e s i r a b l e e f f e c t s so that s i d e e f f e c t s do not n e c e s s a r i l y have to accompany e f f e c t i v e bronchodilation. In order to p l a c e a p a t i e n t i n the optimal range the dose of t h e o p h y l l i n e must be i n d i v i d u a l i z e d , and t h i s i s best done by a d j u s t i n g dose to optimal serum l e v e l s . Even though advanced technology with HPLC and UV s p e c t r o photometry has f a c i l i t a t e d serum determinations i n the c l i n i c a l l a b o r a t o r y as w e l l as the o f f i c e , the procedure i s s t i l l c o s t l y and inconvenient and considered a drawback to the use of the drug. I n d i v i d u a l s vary i n t h e i r serum t h e o p h y l l i n e l e v e l s because t h e i r r a t e s of metabolism d i f f e r . Theophylline undergoes extensive metabolism (Figure 2) by l i v e r microsomal enzymes (4). Less than 10% i s excreted unchanged. The other 90% p l u s i s metabolized through demethylation i n the 1- and 3- p o s i t i o n s and o x i d a t i o n i n the 8- p o s i t i o n to be excreted as a mixture of 3-methylxanthine, 1-methyluric a c i d , and 1,3-dimethyluric a c i d . While the average serum h a l f - l i f e i n the a d u l t may be approximately f i v e hours, the range may vary from one hour i n some i n d i v i d u a l s to 10 hours i n others; hence, there i s v a r i a b i l i t y i n serum l e v e l s . F a c t o r s such as age, h e a l t h , body weight, d i e t , concurrent drug ( i n c l u d i n g t h e o p h y l l i n e ) tobacco, and a l c o h o l use, can cause c o n s i d e r a b l e v a r i a n c e i n t h e o p h y l l i n e h a l f - l i f e . This metabolic scheme provides a s t a r t i n g 1>asis f o r a p p r e c i a t i n g what needs to be done s y n t h e t i c a l l y to make a more b i o l o g i c a l l y s t a b l e form of b r o n c h o d i l a t o r drug. L a t e r , a t t e n t i o n w i l l turn to some s t r u c t u r e s that might not be s u s c e p t i b l e to the same metabolic r o u t e s . There are other f a c t o r s besides metabolism which govern the length of stay of an o r a l dose of drug i n the b o d y — namely, r a t e and extent of a b s o r p t i o n and e l i m i n a t i o n . As regards the former, s u s t a i n e d - r e l e a s e f o r m u l a t i o n can prolong the e f f e c t i v e l i f e of a dose of t h e o p h y l l i n e by prolonging i t s a b s o r p t i o n from the i n t e s t i n a l t r a c t . T h i s technology avoids the many peaks and v a l l e y s i n serum l e v e l s that occur i n the course of frequent dosing w i t h immediate-release products and a l s o lengthens the dosing i n t e r v a l . There are now s e v e r a l s u s t a i n e d - r e l e a s e t h e o p h y l l i n e products on the market. Some of these, however, may not o f f e r s u b s t a n t i a l b e n e f i t over the standard t h e o p h y l l i n e products. I l l u s t r a t e d i n F i g u r e 3 i s a l i k e l y o v e r - a l l mechan i s t i c r o l e of t h e o p h y l l i n e i n asthma. E x t r i n s i c or immed i a t e h y p e r s e n s i t i v i t y - t y p e asthma begins with an antigen antibody complex a t mast c e l l s and r e s u l t s i n the r e l e a s e of chemical mediators which a f f e c t c e l l s i n airways. Smooth muscle c e l l s c o n t r a c t , c a p i l l a r i e s leak, and s e c r e t o r y c e l l s hypersecrete to g i v e a t r i a d of bronchospasm, edema and i n c r e a s e d mucous, r e s p e c t i v e l y . Shown i s the two-enzyme


DRUGS A F F E C T I N G T H E RESPIRATORY

SYSTEM


288

1-METHYLURIC ACID (17%) Figure 2.

Qualitative and quantitative aspects of the metabolic conversion of theophylline by liver microsomal enzymes


14.

SEiDEHAMEL

AND TEMPLE



system that governs the i n t r a c e l l u l a r steady s t a t e l e v e l of c y c l i c AMP. Theophylline i n h i b i t s phosphodiesterase causing the accumulation of c y c l i c AMP. In the smooth muscle c e l l t h i s n u c l e o t i d e promotes r e l a x a t i o n g i v i n g r i s e to bronchod i l a t i o n which opposes any bronchospasm. There i s growing evidence (3,5) to support a second s i t e of a c t i o n of theophyll i n e , i n the mast c e l l s . By causing e l e v a t i o n of c y c l i c AMP i n these c e l l s , t h e o p h y l l i n e can i n h i b i t the r e l e a s e of mediators as does cromolyn sodium and prevent or attenuate the e n t i r e t r i a d of events f o r an o v e r a l l greater b e n e f i t to the p a t i e n t s than through b r o n c h o d i l a t i o n alone. Observations w i t h t h e o p h y l l i n e over the past 10 to 15 years have l e d to a b e t t e r understanding of the u n d e r l y i n g problems and f e a t u r e s of the drug and hence i t s more r a t i o n a l use w i t h i n the l a s t few years. Today, t h e o p h y l l i n e i s a much harder drug to surpass than i t was s e v e r a l years ago. C e r t a i n l y , the f o l l o w i n g features are i n i t s f a v o r : e f f e c t i v e n e s s i n acute and chronic asthma; s a f e t y when dosed p r o p e r l y ; long a c t i o n and t w i c e - d a i l y dosing when given i n s u s t a i n e d - r e l e a s e form; low c o s t . In i t s d i s f a v o r are: p a t i e n t - t o - p a t i e n t v a r i a b i l i t y i n i t s metabolism; need to i n d i v i d u a l i z e dosage; narrow serum l e v e l range between b r o n c h o d i l a t o r e f f e c t s and s i d e e f f e c t s ; g a s t r o i n t e s t i n a l irritation. For years there have been s y n t h e t i c e f f o r t s to make new and b e t t e r t h e o p h y l l i n e - l i k e b r o n c h o d i l a t o r drugs. There have been many attempts to modify the b a s i c t h e o p h y l l i n e molecule with v a r i o u s f u n c t i o n a l group s u b s t i t u t i o n s . D y p h y l l i n e or 7-dihydroxypropyl t h e o p h y l l i n e (see F i g u r e 4) was synthesized i n the 1940's (6). I t has been r e c e i v i n g more a t t e n t i o n i n the U.S. as a drug (7,8,9). Often confused as a t h e o p h y l l i n e s a l t , d y p h y l l i n e i s a d i s t i n c t chemical e n t i t y . T y p i c a l of many 7 - a l k y l s u b s t i t u t e d t h e o p h y l l i n e s , i t has a low i n c i d e n c e of s i d e e f f e c t s but a l s o a low l e v e l of a c t i v i t y and short d u r a t i o n of a c t i o n . R e p r o t e r o l i s a beta-phenethylaminoalkylxanthine r e c e n t l y marketed abroad. I t represents a chemical h y b r i d of t h e o p h y l l i n e and e i t h e r t e r b u t a l i n e or metaproterenol (Figure 4). T h i s agent has a p r e f e r e n t i a l impact on b e t a adrenergic receptors and can be c l a s s i f i e d as a b e t a ~ adrenergic stimulant (10). R e p r o t e r o l i s claimed not to e x h i b i t the CNS and c a r d i o v a s c u l a r e f f e c t s t y p i c a l of other beta-adrenergic stimulants, suggesting that the t h e o p h y l l i n e moiety may be important to t h i s molecule. Many compounds have r e s u l t e d from the s u b s t i t u t i o n of t h i o , amino and l a r g e a l k y l groups on the t h e o p h y l l i n e molecule. But f o r the most p a r t , these have shown good i n v i t r o b r o n c h o d i l a t o r potency which does not c a r r y over i n t o i n v i v o t e s t s (11). (For t h i s c l a s s of drugs, experience d i c t a t e s that i n v i t r o t e s t i n g should not alone be the guide 2



290

SYSTEM

MAST CELL ι + Antigen-Antibody

Phosphodiesterase

Mediators


^ Relaxation

AIR

WAYS

(Bronchodilation)

SMOOTH MUSCLE

•+ Contraction ( Broncho spasm )

CAPILLARIES

-*• J Permeability (Edema) Stimulation ( j Mucus)

SECRETORY CELLS

Figure 3. Likely mechanistic role of theophylline in asthma. By inhibition of phosphodiesterase and subsequent elevation of cyclic AMP in mast cells and air way smooth muscle, theophylline is shown to have an overall beneficial effect on airways in asthma.

OH I

DYPHYLLI NE

OH

CH 0

(ÇH ) 2

3

N H

-CH -ÇH^\\ 2

I CH

3

Figure 4. REPR0TER0L


14.

SEiDEHAMEL

AND TEMPLE



to synthesis.) One m u l t i - s u b s t i t u t e d t h e o p h y l l i n e molecule w i t h promise w i l l be discussed l a t e r . Some major innovations i n t h e o p h y l l i n e - l i k e agents, e s p e c i a l l y i n terms of new chemical s t r u c t u r e , are found i n s e v e r a l new h e t e r o c y c l i c types of compounds. These i n c l u d e p u r i n e s , p y r i m i d i n e s , benzopyranopyridines, q u i n a z o l i n e s and pyridobenzodiazepines (Compounds I - XI, F i g u r e 5). Showing v a r y i n g degrees of s t r u c t u r a l resemblance to t h e o p h y l l i n e , many of these compounds are potent b r o n c h o d i l a t o r agents i n man and/or animals. Some, through i n h i b i t i o n of phosphod i e s t e r a s e and subsequent e l e v a t i o n of c y c l i c AMP, relax b r o n c h i a l smooth muscle. A few, however, have other potent i a l l y u s e f u l antiasthma p r o p e r t i e s . Compounds I and I I , r e s p e c t i v e l y , are some 15 and 10 times as potent as t h e o p h y l l i n e as b r o n c h o d i l a t o r s when administered to guinea p i g s by the o r a l route (12,13,14). They do not e x h i b i t the c a r d i a c s t i m u l a t o r y p r o p e r t i e s of theophylline. In a d d i t i o n , to b r o n c h o d i l a t o r a c t i o n , compound I I possesses, as p r e d i c t e d from i t s t r i c y c l i c s t r u c t u r e , a n t i h i s t a m i n i c and p o s s i b l y even some mediator r e l e a s e i n h i b i t o r p r o p e r t i e s which could compliment i t s o v e r a l l u t i l i t y i n a l l e r g i c airways d i s e a s e . Compound I I I has a remarkably greater o r a l bronchod i l a t o r potency i n animals than does t h e o p h y l l i n e (15). Not only does t h i s agent i n h i b i t phosphodiesterase, but i t a l s o appears to s t i m u l a t e beta-adrenergic r e c e p t o r s , the end r e s u l t of both a c t i o n s being a complimentary c y c l i c AMP induced b r o n c h i a l smooth muscle r e l a x a t i o n . Compound IV, which represents perhaps one of the simplest b r o n c h o d i l a t o r s t r u c t u r e s , i s somewhat more potent as a b r o n c h o d i l a t o r i n guinea p i g s than i s t h e o p h y l l i n e (16,17). L i k e the other agents described thus f a r , i t too i n h i b i t s phosphodiesterase. The c a r d i o v a s c u l a r and CNS p r o f i l e s of t h i s compound have not been described. Compound V has advanced to the stage of i n v e s t i g a t i o n i n man (18). In s p i t e of i t s encouraging pharmacologic p r o f i l e i n animals, however, i t was found i n asthmatics to have no potency advantage over t h e o p h y l l i n e . Furthermore, the compound caused considerable drowsiness, an a c t i o n most l i k e l y a t t r i b u t e d to i t s known a n t i h i s t a m i n i c e f f e c t s . Compound VI has b r o n c h o d i l a t o r a c t i v i t y when administered by the intravenous route (19). I t s potency r e l a t i v e to t h e o p h y l l i n e has not been reported. T h i s compound does not appear to possess c a r d i a c s t i m u l a t o r y a c t i o n but i t does have an expectorant a c t i o n which could prove to be of value when the airways are obstructed with tenacious mucous. I n t e r e s t i n the xanthine moiety has, f o r the most p a r t , centered on b r o n c h o d i l a t o r a c t i v i t y . As described e a r l i e r , t h e o p h y l l i n e has a mixture of b r o n c h o d i l a t o r and a n t i a l l e r g y components. By p r o g r e s s i v e m o d i f i c a t i o n s of methylxanthines,


291

292


SYSTEM

Bronchodilator Compounds


0

IV

Br PFIZER 0

\ H ( C H

V

WARNER-LAMBERT

1029^ A

VI

3

BOEHRINGER INGELHEIM

Figure 5.


)

2

14.

SEiDEHAMEL AND TEMPLE



Antiallergic Compounds

VII

MAY & BAKER 22,9^8

VIII

BOEHRINGER MANNHEIM 06.001

Antiallergic ( Bronchodilator ) Compounds

CH X

3

CH CH 2

3

COOPER CK-O383

0

CI XI

MEAD JOHNSON Figure 5.

12504

(Continued).


293


294


SYSTEM

compound V I I evolved. I t possesses strong a n t i a l l e r g i c e f f e c t s v i a mediator r e l e a s e i n h i b i t i o n but e s s e n t i a l l y no b r o n c h o d i l a t o r e f f e c t s (20). This compound represents an e a r l y example of a potent o r a l l y a c t i v e cromolyn-like compound. Another more recent molecule w i t h t h i s same p r o f i l e and resemblance to t h e o p h y l l i n e i s compound VIII which, u n l i k e V I I , i s a l s o a potent a n t i h i s t a m i n i c agent (21). These "pure mediator r e l e a s e i n h i b i t o r s " are discussed elsewhere i n t h i s symposium. There are other compounds i n the l i t e r a t u r e which seem to have a p o t e n t i a l l y u s e f u l blend of bronchodilator and a n t i a l l e r g y a c t i o n . Compound IX, having a cromolyn-type s t r u c t u r e , i s e f f e c t i v e i n the passive cutaneous anaphylaxis t e s t i n r a t s as w e l l as i n the histamine a e r o s o l t e s t i n guinea p i g s (22). I t has l e s s c a r d i o v a s c u l a r e f f e c t s than t h e o p h y l l i n e but causes some CNS s t i m u l a t i o n . Compound X i s a recent compound which i n animals appears to be more potent than t h e o p h y l l i n e i n i t s b r o n c h o d i l a t o r / a n t i a l l e r g i c a c t i o n s and a l s o appears to have greater b r o n c h o - s e l e c t i v i t y (23, 24). I t seems to be somewhat more a c u t e l y t o x i c than t h e o p h y l l i n e . Compound X could, as a r e s u l t of the s u b s t i t u e n t s i n p o s i t i o n s otherwise v u l n e r a b l e to demethylation and o x i d a t i o n metabolic r e a c t i o n s , be a more b i o l o g i c a l l y s t a b l e molecule than t h e o p h y l l i n e . I t i s now undergoing c l i n i c a l t r i a l s . Research i n r e s p i r a t o r y disease at Mead Johnson has centered on h e t e r o c y c l i c molecules having a mixture of b r o n c h o d i l a t o r and a n t i a l l e r g i c a c t i o n s . One of these, an imidazopurinone (compound X I ) , r e c e n t l y emerged with part i c u l a r l y i n t e r e s t i n g pharmacologic f e a t u r e s . Illustrated i n F i g u r e 6 a r e dose-response curves f o r intraduodenally administered compound XI i n three appropriate t e s t s i n r a t s . The compound i n h i b i t s the passive cutaneous anaphylaxis (PCA) r e a c t i o n , methacholine-induced bronchospasm and allergen-induced bronchospasm i n d i c a t i v e of both bronchod i l a t o r and a n t i a l l e r g i c a c t i v i t y . Of these three t e s t s , the f i r s t i s probably the l e a s t p r e d i c t i v e and the l a s t the most p r e d i c t i v e of antiasthma a c t i v i t y i n man. Interesti n g l y , i t i s i n the allergen-induced bronchospasm t e s t (see Table 1) that compound XI shows a 15-fold greater potency over aminophylline ( t h e o p h y l l i n e ethylenediamine). The d u r a t i o n of a c t i o n of compound XI i s a t l e a s t h a l f - a g a i n as long as that of aminophylline, suggesting greater b i o l o g i c stability. I t appears to be non-tachyphylactic upon r e peated a d m i n i s t r a t i o n , and does not e x h i b i t antihistamine or antiserotonin a c t i v i t y . Bronchodilator a c t i o n has been confirmed i n dogs. Under i n v i t r o c o n d i t i o n s , compound XI i s more potent than aminophylline i n r e l a x i n g airway smooth muscle and i n i n h i b i t i n g phosphodiesterase and histamine r e l e a s e from mast c e l l s . At b r o n c h o d i l a t o r doses there are no a p p r e c i a b l e d i f f e r e n c e s between compound XI and aminophylline


S E i D E H A M E L AND TEMPLE


100


295

r

.03

0.1

0.3

1

3

10

DOSE (Mg/Kg. Intraduodenal)

Figure 6. Dose vs. antiallergic and/or bronchodilator effects of MJ 12504 in three appropriate tests in rats. Points represent mean values from 4 to 14 animals per dose level. Vertical bars represent SE of the means. (Φ) allergen-induced bronchospasm; (O) methacholine-induced bronchospasm; (A) PC A reaction.


30

DRUGS A F F E C T I N G T H E RESPIRATORY S Y S T E M

296

TABLE I SUMMARY OF


PCA

a

RAT

BRONCHODILATOR

RAT

"ASTHMA"

DOG G.P

5

0

BRONCHODILATOR TRACHEA

12 5 04

Ρ 0 Τ I: Ν C Y

1

0

e

RAT

LUNG PDE

(cAMP)

RAT

MAST

g

RAT

CARDIOVASCULAR

CELL

f

I.D.

8.«+±1.1

I.D.

5.2±1.3

I.D.

0.90±0.5

I.D.

3.1±1.5

-

VITRO

IC =U90MM

1

50

1

Drugs Affecting the Respiratory System - ACS Publications - American

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