Introduction: Bronchodilators and Other Pharmacodynamic Agents

11 Introduction: Bronchodilators and Other Pharmacodynamic Agents

Downloaded by UNIV OF SYDNEY on May 28, 2018 | https://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch011

DAVIS L. TEMPLE, JR. Mead Johnson Pharmaceuticals, Evansville, IN 47721 The first section of this book deals with drugs which inhibit the immunologically-induced release of mediators of anaphylaxis from certain target cells such as mast cells and polymorphonuclear neutrophils. Such drugs thus would be expected to be useful for the treatment of asthma and related atopic disease in a purely prophylactic sense. Since asthma is a multipartite disease, or even a family of diseases of varied etiology, simple inhibition of immunologically-induced mediator release may not be sufficient to prevent clinical manifestations. Thus it is necessary to consider other pharmacodynamic agents as useful antiasthma drugs. The second section of this book deals with such drugs, which may block mediator release, but also act to inhibit the consequences of mediator release or other bronchospastic stimulation. Such drugs could then provide therapeutic utility beyond the often incomplete prophylactic actions of mediator release inhibitors. Figure 1 shows proposed interrelationships between the various anaphylactic substances and control of smooth muscle tone and secretory processes. Although somewhat o v e r s i m p l i f i e d , t h i s diagram provides a framework f o r determining s i t e s f o r drug i n t e r a c t i o n as w e l l as f o r proposing mechanisms o f a c t i o n . Accordi n g to t h i s scheme, histamine, ECF-A, SRS-A, k a l l i k r e i n , and PAF are the primary mediators of anaphylaxis r e l e a s e d from mast c e l l s , whereas the prostaglandins (which a r e s e n s i t i z e d de novo f o l l o w i n g an appropriate stimulus) and b r a d y k i n i n a r e secondary mediat o r s o f anaphylaxis. Likewise, leukocytes r e l e a s e other c o n s t r i c t i v e , chemotactic, and p r o t e o l y t i c substances which p l a y c r u c i a l r o l e s i n asthma, b r o n c h i t i s , emphysema, and other r e s p i r a t o r y disease. P a t i e n t s with chronic o b s t r u c t i v e pulmonary disease (COPD) such as chronic b r o n c h i t i s and emphysema may possess exc e s s i v e p r o t e o l y t i c enzyme a c t i v i t y which have a part i n t i s s u e d e s t r u c t i o n . The e s t e r o l y t i c enzyme e l a s t a s e , which i s a l y s o s o mal enzyme derived from n e u t r o p h i l i c polymorphonuclear leukocytes, has been shown to be the primary p r o t e o l y t i c enzyme i n v o l v e d i n the p r o g r e s s i v e a l v e o l a r w a l l d e s t r u c t i o n c h a r a c t e r i s t i c o f emphysema. The e f f e c t s of e l a s t a s e are normally held i n check by the 0-8412-0536-l/80/47-118-211$05.00/0 © 1980 American Chemical Society

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

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

/

H

SYSTEM

IRRITANT RECEPTOR VAGUS


HISTAMINE RECEPTOR

CNS

Τ

HISTAMINE ECF-A SRS-A KALLIKREIN PAF

ADRENAL MEDULLA

ι

MAST CELL

ACH CONTRACTION

PG's BRADYKININ ANTIGEN " CHALLENGE

GMP

AMP

IrunJ cGMP PDE

cAMP PDE

ACH RECEPTOR a-ADRENERGIC RECEPTOR

tcGMP

trAMP

LJ

îcAMP

h-H

/^-ADRENERGIC I RECEPTOR

Κ

POLYMORPHONUCLEAR NEUTROPHILS, EOSINOPHILS, AND BASOPHILS RELAXATION

CONSTRICTIVE, CHEMOTACTIC, AND PROTEOLYTIC SUBSTANCES

Figure 1.

TOTAL CATECHOLAMINE POOL EPINEPHRINE & NOREPINEPHRINE

Interrehtionships between the various anaphylactic substances and control of smooth muscle tone and secretory processes



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presence of protease i n h i b i t o r enzymes, of which α ^ - a n t i t r y p s i n i s the most important. L o c a l a l v e o l a r p r o t e a s e - a n t i p r o t e a s e imbal ances due to c i g a r e t t e smoke or genetic OL - a n t i t r y p s i n d e f i c i e n c y may develop and r e l a t e to the pathogenesis of COPD. Thus, an e f f e c t i v e , nontoxic e l a s t a s e i n h i b i t o r would p o t e n t i a l l y represent a u s e f u l drug f o r the treatment of COPD. A c c r e t i o n of a v i s c i d mucus i s the hallmark of the more c h r o n i c forms of o b s t r u c t i v e pulmonary d i s e a s e . The presence of the mucus exacerbates the pathology both by p r o v i d i n g a mechanical block to the i n s p i r a t i o n and e x p i r a t i o n of a i r and by preventing t o p i c a l drugs from reaching the d i s t a l b r o n c h i . Although not u n i v e r s a l l y accepted, therapy which w i l l l i q u i f y the mucus so that i t can be expectorated should have a p l a c e i n the treatment of COPD. S u l f h y d r y l drugs such as N - a c e t y l c y s t e i n e are a v a i l a b l e f o r t h i s use. For the purposes of t h i s d i s c u s s i o n , we w i l l consider h i s t a mine as the mediator of anaphylaxis. The importance of t h i s sub stance i n asthma and r e s p i r a t o r y disease i s w e l l documented. As shown i n F i g u r e 1, histamine may act at e i t h e r a histamine or a n o n s p e c i f i c receptor s i t e to produce d i r e c t smooth muscle c o n t r a c t i o n or more importantly v a g a l r e f l e x smooth muscle c o n t r a c t i o n . Although the c l a s s i c a l a n t i h i s t a m i n e s have long been known to be of value i n the treatment of the symptoms of v a r i o u s a l l e r g i c con d i t i o n s , they are g e n e r a l l y considered i n e f f e c t i v e i n the t r e a t ment of b r o n c h i a l asthma. We do note, however, that some of the new "second generation" a n t i h i s t a m i n e s such as k e t o t i f e n and oxa tomide are not only c l a s s i c a l histamine a n t a g o n i s t s but are a l s o reported to be e f f e c t i v e i n h i b i t o r s of mediator r e l e a s e , although the mechanism of the l a t t e r a c t i v i t y remains undefined f o r t h i s group of drugs. Histamine-induced v a g a l r e f l e x b r o n c h o c o n s t r i c t i o n i s medi ated via a c e t y l c h o l i n e r e l e a s e at nerve endings i n b r o n c h i . A c e t y l c h o l i n e leads to i n c r e a s e d l e v e l s of cGMP i n b r o n c h i a l smooth muscle and then s e q u e n t i a l l y to c o n s t r i c t i o n . Thus the parasympathetic system i s important i n the airways, p l a y i n g a modulating r o l e i n bronchomotor tone and i n responses to i r r i t a n t s . Various workers have, however, shown that parasympathetic r e f l e x e s are not i n v a r i a b l y a major component of human b r o n c h i a l responses to i n h a l e d antigen. Hence a n t i c h o l i n e r g i c b r o n c h o d i l a t o r drugs may be more u s e f u l i n chronic congestive s t a t e s which l e a d to a high degree of r e f l e x c h o l i n e r g i c s t i m u l a t i o n as seen i n c h r o n i c bronchitis. U n t i l recent years a n t i c h o l i n e r g i c b r o n c h o d i l a t o r drugs were not of great i n t e r e s t f o r use i n the treatment of c h r o n i c o b s t r u c t i v e airway disease - p r i m a r i l y because of uncon t r o l l e d , o f t e n i n a p p r o p r i a t e , use i n the past as w e l l as a h i g h i n c i d e n c e of the overt systemic a n t i c h o l i n e r g i c s i d e e f f e c t s seen with a t r o p i n e usage. Renewed i n t e r e s t i n a n t i c h o l i n e r g i c broncho d i l a t o r drugs was p r e c i p i t a t e d by the i n t r o d u c t i o n of Sch-1000, a t o p i c a l l y - e f f e c t i v e a n t i c h o l i n e r g i c b r o n c h o d i l a t o r drug char a c t e r i z e d by a low i n c i d e n c e of s i d e e f f e c t s when administered by



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the t o p i c a l route. Current work i n t h i s area i s d i r e c t e d a t " n o n - c l a s s i c a l " agents which show s e l e c t i v i t y f o r the b r o n c h i over the s a l i v a r y receptor s i t e . S t i m u l a t i o n of the α-adrenergic r e c e p t o r , l i k e c h o l i n e r g i c s t i m u l a t i o n , leads to a concomitant i n c r e a s e i n cGMP, and hence to increased c o n t r a c t i l i t y of smooth muscle. The presence of α-adrenergic r e c e p t o r s i n t r a c h e a l smooth muscle has been a matter of controversy. Various workers have however demonstrated that sympathomimetic agents w i l l c o n t r a c t human t r a c h e a l smooth muscle in vitro i n the presence o f β-adrenergic b l o c k i n g agents. These observations lend v a l i d i t y to the concept of α-adrenergic recep t o r s p l a y i n g a r o l e i n the maintenance of airway tone. Clinical experience with phentolamine, thymoxamine, indoramine and others has shown mixed r e s u l t s ; the consensus however i s that these drugs may be u s e f u l i n some severe cases of asthma where the a c t i v i t y of α-receptors i s enhanced. A n a p h y l a c t i c c o n d i t i o n s i n the b r o n c h i induce a CNS-mediated r e l e a s e of catecholamines from the adrenal medulla. These c a t e cholamines c o n t r i b u t e to the t o t a l catecholamine p o o l of stored and c i r c u l a t i n g epinephrine and norepinephrine. S t i m u l a t i o n of the 3-adrenergic receptor (adenylate c y c l a s e ) leads to an i n c r e a s e i n cAMP l e v e l s i n both b r o n c h i a l smooth muscle and mast c e l l s to give smooth muscle r e l a x a t i o n and lessened mediator r e l e a s e . This 3-adrenergic receptor s i t e has proven s e n s i t i v e to s y n t h e t i c com pounds which show marked advantages i n terms of o r a l a c t i v i t y , s e l e c t i v i t y (β^ over 3^), and d u r a t i o n o f a c t i o n over epinephrine and i s o p r o t e r e n o l as drugs. These newer agents which a r e d i s cussed i n d e t a i l i n a f o l l o w i n g chapter may not y e t represent op t i m a l agents as they a r e reported to possess a v a r i e t y of d e f i c i t s such as t u m o r i g e n i c i t y and t r e m o r i g e n i c i t y . Just as cAMP l e v e l s a r e enchanced by adenylate c y c l a s e stimu l a t i o n , they are decreased through metabolism of cAMP by cAMP phosphodiesterase. Correspondingly, i n h i b i t i o n of t h i s enzyme leads to increased smooth muscle and mast c e l l i n t r a c e l l u l a r cAMP l e v e l s and hence b r o n c h o d i l a t i o n and i n h i b i t i o n of mediator r e l e a s e . cAMP phosphodiesterase i s i n h i b i t e d by drugs such as theo p h y l l i n e which i s u s e f u l i n the treatment and p r o p h y l a x i s of asthma. Theophylline has seen a recent resurgence i n i n t e r e s t f o r use i n the treatment of asthma p a r t l y due to the development of improved pharmaceutical p r e p a r a t i o n s and to the a v a i l a b i l i t y of convenient methods f o r measuring blood and s a l i v a r y l e v e l s . Theo p h y l l i n e i s i n f a c t now the drug of choice f o r maintenance therapy i n c h r o n i c asthma. Theophylline u n f o r t u n a t e l y remains an unpre d i c t a b l e and e r r a t i c drug with severe t o x i c o l o g i c consequences f o l l o w i n g i n a p p r o p r i a t e or i n c o r r e c t c l i n i c a l use. Therefore, current research i s aimed a t new drugs possessing s i m i l a r p r o f i l e s of a c t i v i t y , but with lessened t o x i c o l o g i c and metabolic d i s a d vantages . Even though many new developments a r e being made i n the area of c l a s s i c a l b r o n c h o d i l a t o r drugs, extensive e f f o r t s a r e a l s o be-


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i n g d i r e c t e d at more recent innovations such as s y n t h e t i c p r o s t a glandins. Prostaglandins and the lungs seem to have a c l o s e i n t e r r e l a t i o n - b r o n c h i a l t i s s u e contains some of the highest p r o s t a g l a n d i n l e v e l s i n the body, of the PGE s which r e l a x b r o n c h i a l smooth muscle, of the PGFa's which c o n s t r i c t b r o n c h i a l smooth muscle, as w e l l as the v a r i o u s products of a r a c h i d o n i c a c i d cascade. Although both c l a s s e s of p r o s t a g l a n d i n s have been shown to i n c r e a s e cAMP l e v e l s in vitro, in vivo b i o l o g i c e f f e c t s ( b r o n c h o d i l a t i o n ) are apparently mediated by d i r e c t s t i m u l a t i o n of adenyl c y c l a s e . I t was demonstrated some time ago that t o p i c a l a p p l i c a t i o n of e i t h e r PGE or PGE produced marked bronchodilation, with the l a t t e r compound Being more potent. These n a t u r a l PGE s are not u s e f u l b r o n c h o d i l a t o r drugs even though they are more potent b r o n c h o d i l a t o r s than i s o p r o t e r e n o l due to upper airway i r r i t a t i o n , r e f l e x b r o n c h o c o n s t r i c t i o n , potent cough i n d u c t i o n , and a very short d u r a t i o n of a c t i o n . These c o n s i d e r a t i o n s have l e d v a r i o u s groups to synthesize p r o s t a g l a n d i n analogs with modi f i c a t i o n s aimed at preventing these problems. A v a r i e t y of pharmacodynamic agents are thus u s e f u l f o r the treatment of r e s p i r a t o r y d i s e a s e . Agents which a f f e c t c y c l i c n u c l e o t i d e systems are important i n the maintenance of airway smooth muscle tone and i n the i n h i b i t i o n of mediator r e l e a s e from mast c e l l s , while other agents act d i r e c t l y on s p e c i f i c enzymes, c e l l s , or s e c r e t i o n s i n v o l v e d i n r e s p i r a t o r y d i s e a s e . The purpose of a l l of these agents that we have discussed i s to i n c r e a s e or r e s t o r e the a b i l i t y of the lung to act as a blood oxygenating organ. Progress has been made i n the area of b r o n c h o d i l a t o r and other r e s p i r a t o r y pharmacodynamic agents i n recent years, some of which i s discussed i n the f o l l o w i n g chapters. 1

2


1

RECEIVED August 6,

1979.


Introduction: Bronchodilators and Other Pharmacodynamic Agents

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