Pro-drugs as Novel Drug Delivery Systems

6 The Effect of a Pro-drug of Epinephrine (Dipivalyl Epinephrine) in Glaucoma—General Pharmacology,

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Toxicology, and Clinical Experience DAVID A. McCLURE Alergan Pharmaceuticals, Irvine, Calif. 92664 Epinephrine has been used for many years in the treatment of the condition called glaucoma. Glaucoma is a disease where the pressure within the eye increases to a point where damage to the visual apparatus occurs and, if left unchecked, could lead to a significant deminuation in visual acuity and eventually, blindness. The reasons for this pressure increase are numerous and we will touch on these shortly. However, first, let us examine the anatomy of the eye and how glaucoma comes about. Figure 1 shows a cross section of an eye. From the crystalline lens backward is one chamber filled with a thick, viscus fluid that does not move. Another chamber, that is in front of the lens and the Zonule ligament, is actually composed of two chambers with fluid circulating between. This fluid is called the aqueous humor. The path of the aqueous humor is from the ciliary body, through the pupil, and out the trabecular meshwork and an area called the Canal of Schlemm. Figure 2 is a close-up of the area of fluid circulation and drainage. Now, we mentioned earlier that glaucoma results from an increase in the intraocular pressure (IOP). The normal IOP averages around 17 mmHg. This pressure can increase in 3 ways: 1) a greater influx of fluid into the envelope of the eye while maintaining a constant outflow, 2) a decreased outflow while maintaining a constant inflow or, 3) a combination of the two. We are concerned primarily (in simple primary glaucoma) with a decrease in the outflow of aqueous fluid. Now what happens if the IOP goes up 10 to 20 mmHg from normal and is maintained at that level? In

224 Higuchi and Stella; Pro-drugs as Novel Drug Delivery Systems ACS Symposium Series; American Chemical Society: Washington, DC, 1975.


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Pro-drug of Epinephrine in Glaucoma

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o t h e r words, why i s glaucoma bad? The p r e s s u r e t h a t i s b u i l t up i n the f r o n t p a r t o f the eye i s r e f l e c t e d t o the back p a r t o f the eye where, o f c o u r s e , the most v i t a l p a r t s o f the eye r e s i d e . Figure 3 i s a photograph o f the r e t i n a . T h i s i s the p o i n t where the o p t i c nerve and b l o o d v e s s e l s emerge. As the p r e s s u r e i n c r e a s e s , the d i s c c o n t a i n i n g the nerve and b l o o d v e s s e l s i s pushed back and a c o n d i t i o n c a l l e d cupping occurs. This r e s u l t s i n a decreased v i s u a l f i e l d ( p e r i p h e r a l ) and as the c o n d i t i o n c o n t i n u e s , v i s i o n gets worse. C h r o n i c s i m p l e glaucoma has been t r e a t e d b o t h m e d i c a l l y and s u r g i c a l l y . M e d i c a l l y , t h e r e are a v a r i e t y o f drugs c u r r e n t l y a v a i l a b l e . These a r e p r i m a r i l y c h o l i n e r g i c agents such as p i l o c a r p i n e and a d r e n e r g i c a g e n t s such as e p i n e p h r i n e . There a r e p r o s and cons f o r the use o f each g r o u p . F o r example, the c h o l i n e r g i c s cause m i o s i s ( i . e . , a s m a l l p u p i l ) and enough accomodative spasm ( i . e . , d e c r e a s e d a b i l i t y to focus) t h a t r e a d i n g i s d i f f i c u l t , d r i v i n g at n i g h t is d i f f i c u l t , etc. In a d d i t i o n , because some c h o l i n e r g i c s do n o t p e n e t r a t e i n t o the eye v e r y w e l l , the f r e q u e n c y o f a d m i n i s t r a t i o n i s a t an i n c o n v e n i e n t , 6 t o 8 times p e r d a y . In a d d i t i o n , because most o f the c h o l i n e r g i c s are e s t e r s o r l a c t o n e s , the h i g h l e v e l o f l o c a l e s t e r a s e enzymes r e q u i r e s the i n c r e a s e d frequency of a d m i n i s t r a t i o n . Even w i t h a l l t h e s e i n c o n v e n i e n c e s , m i o t i c s are used e x t e n s i v e l y and t e n d t o work q u i t e w e l l . T h e i r mechanism o f a c t i o n i s p r o b a b l y v a s o d i l a t i o n which p e r m i t s a g r e a t e r e x i t o f aqueous f l u i d from Schlemm's C a n a l . The main a d r e n e r g i c compound used today i s epinephrine. T h i s compound appears t o have a t w o f o l d e f f e c t on the maintenance o f IOP. The f i r s t i s the b e t a a d r e n e r g i c mechanism w h i c h , s i m i l a r t o the c h o l i n e r g i c a g e n t s , opens up the e p i s c l e r a l b l o o d v e s s e l s p e r m i t t i n g a g r e a t e r f l u i d l o s s from the c a n a l o f Schlemm. T h i s appears t o be b r o u g h t about by the s t i m u l a t i o n o f e p i n e p h r i n e on the b e t a a d r e n e r g i c r e c e p t o r s i n e p i s c l e r a l b l o o d v e s s e l s and a l s o t h o s e r e s i d i n g i n the C a n a l o f Schlemm and perhaps even i n the t r a b e c u l a r meshwork. In a d d i t i o n , e p i n e p h r i n e has a v a s o c o n s t r i c t i v e mechanism, i . e . , the a l p h a a d r e n e r g i c mechanism, which may a c t by d e c r e a s i n g the p r o d u c t i o n o f aqueous f l u i d from the c i l i a r y body.

Higuchi and Stella; Pro-drugs as Novel Drug Delivery Systems ACS Symposium Series; American Chemical Society: Washington, DC, 1975.


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Figure 1

Figure 2

Figure 3 Higuchi and Stella; Pro-drugs as Novel Drug Delivery Systems ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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227

Even though e p i n e p h r i n e appears t o have t h i s unique t w o f o l d mechanism o f a c t i o n , a number o f problems a r i s e , l i k e the c h o l i n e r g i c s , w i t h i t s u s e . T a b l e 1 i l l u s t r a t e s some o f t h e s e p r o b l e m s .


Table 1 Problems o f E p i n e p h r i n e use i n Glaucoma I. II.

III. IV.

Duration of Action Side E f f e c t s A. Ocular B. Systemic Bioavailability Stability

Duration of a c t i o n . When a d m i n i s t e r e d i n t r a v e n o u s l y , the c a r d i o v a s c u l a r , pulmonary and o t h e r e f f e c t s from e p i n e p h r i n e are o v e r w i t h i n 10 m i n u t e s . When i n s t i l l e d i n t o the e y e , a d i l a t e d p u p i l o c c u r s i n 10 t o 15 minutes and the d i l a t i o n l a s t s up t o an hour. The d u r a t i o n o f l o w e r i n g o f IOP from e p i n e p h r i n e can be seen i n F i g u r e 4. The c o n c e n t r a t i o n o f e p i n e p h r i n e (2%) used i n t h e s e d a t a r e p r e s e n t s the highest concentration a v a i l a b l e . It i s presented h e r e t o demonstrate the peak a c t i v i t y time o f 4 hours and a d u r a t i o n o f a c t i o n o f between 12 and 24 h o u r s . The m e t a b o l i c pathways f o r e p i n e p h r i n e can be seen i n F i g u r e 5. The s i d e e f f e c t s o c c u r r i n g from e p i n e p h r i n e t o p i c a l l y a p p l i e d t o the eye are b o t h l o c a l o c u l a r s i d e e f f e c t s and s y s t e m i c . T a b l e 2 i l l u s t r a t e s some of these e f f e c t s . To g e t around a l l t h e s e problems w i t h e p i n e p h r i n e , we were f o r t u n a t e t o get a chance t o examine an analogue o f e p i n e p h r i n e and p o s s i b l y what i s f e l t t o be a p r o - d r u g o f e p i n e p h r i n e . F i g u r e 6 shows the c h e m i c a l s t r u c t u r e o f e p i n e p h r i n e and i t s p r o - d r u g , d i p i v a l y l e p i n e p h r i n e (DPE).


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40


30

-A

20 AVERAGE OF 44 UNTREATED GLAUCOMATOUS EYES

10

1

1

1 TIME (HOURS) Archives of Ophthalmology

Figure 4. Response to 1 drop 2% epinephrine (1)


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Table 2 Ocular Side E f f e c t s

of T o p i c a l Epinephrine

I . Hyperemia Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 13, 2016 | http://pubs.acs.org Publication Date: June 1, 1975 | doi: 10.1021/bk-1975-0014.ch006

II. Mydriasis -r-r-r

^

η

V . Browache (Photophobia)

I I I . C o r n e a l Edema _ _.. . _ . IV. A l l e r g i c S e n s i t i v i t y Systemic I.

V I . Adrenochrome DepOSltS

τ . -,

Side E f f e c t s

V I I . Tolerance VIII.

Maculaopathy

of T o p i c a l Epinephrine

Cardiovascular A . Cardiac Arrhythmias B. Blood Pressure E l e v a t i o n C. Cerebrovascular

II. Pallor,

Dizziness,

III. Fear, Anxiety,

Accidents Tremor

Tenseness,

Restlessness

CH-CH -N 2

CH,

EPINEPHRINE (Mol.Wt. 183.20) CH-CH-.N' ^CH,

DIPIVALYL EPINEPHRINE (DPE,Mol.Wt. 587. 904)

Figure 6


229

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Table 3 Proposed Advantages o f DPE I.


II.

Increased Duration o f A c t i o n Increased B i o a v a i l a b i l i t y

III.

Increased

Potency

IV.

Decreased

Side

V.

Increased

Stability

Effects

T a b l e 3 shows t h e p r o p o s e d advantages o f DPE epinephrine. Why an i n c r e a s e d d u r a t i o n o f a c t i o n w i t h DPE? F i g u r e 7 i l l u s t r a t e s t h e p o s s i b l e r e a s o n f o r an i n creased duration of a c t i o n . The main m e t a b o l i c p a t h way o f e p i n e p h r i n e i s v i a an enzyme c a l l e d c a t e c h o l o - m e t h y l t r a n s f e r a s e (COMT). T h i s enzyme m e t h y l a t e s the meta h y d r o x y l i n e p i n e p h r i n e . T h i s h y d r o x y l , as w e l l as t h e p a r a h y d r o x y l a r e n o t f r e e i n DPE. The p i v a l y l m o i t i é s a r e p r o b a b l y s l o w l y removed by l o c a l e s t e r a s e enzymes so t h a t COMT c a n then a c t . This would t a k e a p r o l o n g e d p e r i o d o f t i m e , thus c a u s i n g a "sustained release" epinephrine. over

ON N CO

CHCHgNHCH

8

NO METANEPHRINE

CHCN NHCH 2

3

NO

3.4 Dl HYDROXY MANDELIC ALDEHYDE



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231

Why an i n c r e a s e d b i o a v a i l a b i l i t y ? I t i s v e r y e v i d e n t t h a t DPE i s much more l i p o p h i l i c than e p i n e p h r i n e by v i r t u e o f t h e two l a r g e p i v a l y l groups a t t a c h e d t o t h e two h y d r o x y l s o f e p i n e p h r i n e . In a d d i t i o n , DPE m a i n t a i n s a h i g h degree o f h y d r o p h i l i c i t y . T h e r e f o r e , by i t s d u a l s o l u b i l i t i e s , i t f i t s i n v e r y n i c e l y t o t h e p r e s e n t day a b s o r p t i o n t h e o r i e s . The c o r n e a o f t h e eye i s t h e b a r r i e r drugs must overcome i n o r d e r t o be absorbed i n t o t h e e y e . The c o r n e a i s composed o f t h r e e l a y e r s : an e p i t h e l i u m and an e n d o t h e l i u m , b o t h o f w h i c h r e q u i r e drugs t o be l i p o p h i l i c i f t h e y a r e t o be absorbed a n d , t h e s t r o m a ; s a n d wiched between t h e e p i t h e l i u m and e n d o t h e l i u m t h a t r e q u i r e d a d r u g t o be h y d r o p h i l i c f o r p e n e t r a b i l i t y . By t h e d u a l s o l u b i l i t y o f DPE, i t s p e n e t r a b i l i t y i n t o the eye i s g r e a t e r t h a n t h e l e s s l i p o p h i l i c e p i n e phrine molecule.

• 20,

TIME IN HOURS

Figure 8. Comparison of IOP effects in rabbits

Why an i n c r e a s e d potency? I f more m a t e r i a l g a i n s a c c e s s t o t h e i n s i d e o f t h e eye i t w i l l t h e n , on a r e l a t i v e b a s i s , be more p o t e n t . F i g u r e 8 shows a comparison between 0.5% e p i n e p h r i n e and 0.16% DPE DPE on t h e IOP o f u n a n e s t h e t i z e d r a b b i t s . The e f f e c t s


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are o b v i o u s . F i g u r e 9 i l l u s t r a t e s a dose-response o f DPE on c a u s i n g p u p i l l a r y d i l a t i o n .


On t h e d i f f e r e n t i a l s i d e e f f e c t s t u d i e s , a comparison o f DPE t o e p i n e p h r i n e r e l a t i v e t o b l o o d

bJ 01

*

If

4

5

6

7

TIME-(HOURS)

j» < kl

Figure 9. Mean percent differences in mydriatic response between treated eyes and control eyes when treated with DPE: 0.20% (O), 0.25% (Π),0.30% (A),0.40% (O),I.O0% (·)

p r e s s u r e and h e a r t r a t e e f f e c t s a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n was c a r r i e d o u t i n dogs and c a t s . F i g u r e s 10 and 11 compare t h e e f f e c t s o f i n t r a v e n o u s l y a d m i n i s t e r e d DPE and e p i n e p h r i n e on t h e b l o o d p r e s s u r e and h e a r t r a t e i n a n e s t h e t i z e d d o g s . I t i s e v i d e n t t h a t DPE has s i g n i f i c a n t l y l e s s e f f e c t on b l o o d p r e s s u r e and h e a r t r a t e t h a n e p i n e p h r i n e . In a s i m i l a r f a s h i o n , t h e e f f e c t o f DPE and e p i n e p h r i n e on t h e b l o o d p r e s s u r e o f a n e s t h e t i z e d a t r o p i n i z e d c a t s may be seen i n F i g u r e 12.



MCCLURE


TIME (MINUTES)

Figure 10. Εfeet of I.V. epinephrine and DPE on blood pressure in dogs

Figure 11. Effect of I.V. epinephrine and DPE on heart rate in dogs


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PRO-DRUGS


DPE i s , t h e n , about 100 t o 400 times weaker than e p i n e p h r i n e i n a f f e c t i n g the c a r d i o v a s c u l a r systems o f dogs and c a t s . I t i s about 100 times more p o t e n t t h a n e p i n e p h r i n e i n i t s a b i l i t y t o lower IOP.

DOSE (XIO-SMOLES/KC) Figure 12. The effect of epinephrine and DPE on the arterial blood pressure of the anesthetized atropinized cat

F i n a l l y , t h e e f f e c t o f DPE on humans w i t h glaucoma may be seen i n F i g u r e 13. I t c a n be seen t h a t t h e response e l i c i t e d by DPE i s p r o n o u n c e d . If one s u b t r a c t s t h e c o n t r a l a t e r a l c o n t r o l eye (normal d i u r n a l response) from t h e t r e a t e d e y e , i t c a n be see t h a t DPE produced a marked r e d u c t i o n i n IOP.



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Pro-drug of Epinephrine in Glaucoma 235

Summary The dipivalyl analogue of epinephrine has been shown to produce fewer side effects and greater potency than the parent compound. These results have been found in both animal and human studies. More studies are to be carried out which will amplify these data and perhaps lead to a better understanding of the mechanism of action of this epinephrine prodrug. Literature Cited 1. L. L. Garner, W. W. Johnstone, E. J. Ballintine, M. E. Carroll, Arch Opth. (1959), 62, 230.


Pro-drugs as Novel Drug Delivery Systems

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