Calcium Antagonism and Antiepileptic Drugs - American Chemical

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Calcium Antagonism and Antiepileptic Drugs JAMES A. FERRENDELLI Washington University Medical School, Division of Clinical Neuropharmacology, Department of Neurology and Neurological Surgery and Department of Pharmacology, St. Louis, MO 63110

The mechanisms of action of most antiepileptic drugs presently in use are poorly understood. However, it is generally agreed that their anticonvulsant effect are probably due to some action on neurotransmission or a direct action on membrane function, particularly ionic conductances, or both in CNS. We have attempted to evaluate the influence of antiepileptic drugs on calcium conductance in brain tissue. Studies of the effects of phenytoin on Ca permeability in isolated nerve terminals (synaptosomes) indicate that this drug inhibits depolarization induced Ca uptake. It appears to selectively reduce sodium permeability and, as a result of this, diminish the degree of membrane depolarization, thus, indirectly, reducing stimulus-coupled Ca accumulation. Phenytoin also inhibits Ca uptake by a sodium-independent process, and we suggest that this may be a result of its presence in cellular membranes and physically distorting their organization. Carbamazepine and lidocaine have effects on Ca conductances similar to those of phenytoin, but other antiepileptic drugs are relatively ineffective. These data, in conjunction with other reported results, lead to the conclusion that the anticonvulsant actions of phenytoin, carbamazepine and lidocaine are partially due to actions on ionic (Na and Ca) permeability in nervous tissue. The relationship between this mechanism and the selective clinical effects of antiepileptic drugs is discussed. Primary, commonly used antiepileptics include phenytoin, phénobarbital, primidone, carbamazepine, ethosuximide and valproic acid. In addition, two benzodiazepines, diazepam and 0097-6156/82/0201-0143$06.00/0 © 1982 American Chemical Society

In Calcium Regulation by Calcium Antagonists; Rahwan, Ralf G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


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clonazepam, are used e x t e n s i v e l y to t r e a t s e i z u r e d i s o r d e r s . These compounds represent s i x d i f f e r e n t chemical c l a s s e s and thus may be expected to have d i v e r s e a c t i o n s . However, the mechanisms of action of antiepileptic drugs are poorly understood at the present time. Presently, available information suggests that augmentation of inhibitory neurotransmission and alteration of ionic conductances i n e x c i t a b l e membranes may be important f o r the a n t i e p i l e p t i c e f f e c t s of many a v a i l a b l e drugs. The r e l a t i o n s h i p betwen anticonvulsant drugs and calcium i s of p a r t i c u l a r i n t e r e s t . Studies in our laboratory have suggested that some antiepileptic drugs a f f e c t calcium conductances i n nervous t i s s u e and may a l s o a f f e c t other i o n i c conductances ( Ι ^ ) · The present report reviews these studies and a hypothesis e x p l a i n i n g the r o l e calcium antagonism i n a n t i e p i l e p t i c drug mechanism i s presented. Experimental

Methods

In the experiments described i n this report calcium conductance was measured i n nerve terminals (synaptosomes) i s o l a t e d from r a t c e r e b r a l cortex. Calcium conductances i n these subcellular particles have been characterized and described e x t e n s i v e l y by B l a u s t e i n and colleagues and i t appears that synaptosomes possess many of the p r o p e r t i e s of i n s i t u nerve terminals (^~_7). B r i e f l y , synaptosomes were prepared (8) and calcium uptake was measured i n the f o l l o w i n g manner. Four r a t s were k i l l e d by a s p h y x i a t i o n and t h e i r brains were r a p i d l y removed and placed in ice-cold 0.32 M sucrose. The forebrains, excluding o l f a c t o r y bulbs, were homogenized i n 5 volumes of sucrose i n a teflon-glass homogenizer. A f t e r c e n t r i f u g a t i o n to remove nuclei and debris, the synaptosomes were isolated by differential centrifugation in a discontinuous sucrose gradient. I c e - c o l d b u f f e r , which was i d e n t i c a l to c o n t r o l b u f f e r (see below) except that i t contained only 0.02 mM C a C l , was slowly added to the 0.8 M sucrose f r a c t i o n enriched with synaptosomes to adjust the sucrose concentration to 0.32 M. Synaptosomes were recovered by c e n t r i f u g a t i o n and suspended i n c o n t r o l b u f f e r c o n t a i n i n g 132 mM NaCl, 5 mM KC1, 1.2 mM each of C a C l , MgCl and NaH P0^, 2 mM t r i s , and 10 mM glucose, pH 7.4, to give a f i n a l concentration of 1.2-1.6 mg prot/ml. 2

2

2

2

A l i q u o t s (0.5 ml) of synaptosomal suspension were preincubated f o r 25 min at 30 C. When e f f e c t s of drugs were examined, they were added to the synaptosomal suspension at the beginning of the preincubation period at various con centrations. Following preincubation C a uptake was i n i t i a t e d by the a d d i t i o n of 0.5 ml of one of the f o l l o w i n g s o l u t i o n s , each c o n t a i n i n g 0.5 \iC± C a C l / m l : (1) c o n t r o l b u f f e r ; (2) e

5

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control buffer containing various concentartions of v e r a t r i d i n e ; (3) a buffer i d e n t i c a l t o c o n t r o l b u f f e r except that i tcontained 17 mM N a C l and 120 mM KC1. I n e x p e r i m e n t s where e f f e c t s o f d r u g s were e x a m i n e d , t h e y were i n c l u d e d i n these buffers a t designated concentrations. I n some e x p e r i m e n t s ( s e e r e s u l t s ) , M n C l o r t e t r o d o t o x i n was i n c l u d e d in the buffers. Following i n c u b a t i o n i n the presence a t Ca for v a r i o u s times as i n d i c a t e d i n t h e r e s u l t s s e c t i o n , uptake was t e r m i n a t e d by t h e r a p i d a d d i t i o n o f 6 m l o f i c e - c o l d s t o p b u f f e r c o n t a i n i n g 132 mM N a C l , 5 mM KC1, a n d 3 mM EGTA a d j u s t e d t o pH 7.4 w i t h t r i s b a s e . Immediately f o l l o w i n g t h i s the s u s p e n s i o n was f i l t e r e d through g l a s s fiber f i l t e r s (GF/A Whatman, I n c . ) . The f i l t e r s were washed w i t h a n a d d i t i o n a l s t o p b u f f e r a n d t h e n p l a c e d i n g l a s s v i a l s c o n t a i n i n g 10 m l o f s c i n t i l l a t i o n c o c k t a i l ( S c i n t i v e r s e , F i s h e r S c i e n t i f i c Co.) a n d counted i n a liquid scintillation counter. Results were expressed as stimulated calcium uptake, which i s the a c c u m u l a t i o n o f Ca i n t h e p r e s e n c e o f v e r a t r i d i n e o r h i g h Κ minus t h e uptake i n c o n t r o l b u f f e r .


2

C h a r a c t e r i s t i c s o f C a l c i u m U p t a k e i n Synaptosomes Addition o f ^ C a t o synaptosomes i n c u b a t e d i n c o n t r o l b u f f e r ( 1 3 2 mM Na, 5 mM K) r e s u l t s i n a r a p i d u p t a k e o f t h e isotope during the f i r s t f i v e seconds, a slower accumulation for t h e n e x t 25 s e c o n d s , a n d v e r y l i t t l e o r no a d d i t i o n a l uptake t h e r e a f t e r . I n c r e a s i n g t h e [K] i n t h e i n c u b a t i o n m e d i a m a r k e d l y augments Ca u p t a k e . This s t i m u l a t o r y e f f e c t o f Κ seems t o o c c u r i m m e d i a t e l y a n d i s e s s e n t i a l l y c o m p l e t e w i t h i n t h e f i r s t 30 s e c . V e r a t r i d i n e a l s o i n c r e a s e s s y n a p t o s o m a l Ca u p t a k e , b u t i t s o n s e t o f a c t i o n i s s l o w e r t h a n t h a t o f Κ and r e q u i r e s 3 min o r longer f o r completion. The maximum e f f e c t o f veratridine i s s i m i l a r t o that o f K, h o w e v e r , a n d t h e s t i m u l a t o r y e f f e c t o f b o t h Κ and v e r a t r i d i n e on Ca u p t a k e a r e concentration-dependent. Tetrodotoxin, at concentrations o f 10""^ M o r g r e a t e r , b l o c k s t h e a c t i o n o f v e r a t r i d i n e 9 0 % b u t h a s no e f f e c t on t h e a c t i o n o f K, e v e n a t c o n c e n t r a t i o n s up t o 10 M (Figure 1). I n c o n t r a s t , Mn i n h i b i t s Ca u p t a k e s t i m u l a t e d by v e r a t r i d i n e and Κ i n s i m i l a r f a s h i o n s , w i t h a n a p p a r e n t I D Q Q o f 1 mM f o r b o t h a n d e s s e n t i a l l y c o m p l e t e b l o c k a d e a t 10 mM ( F i g u r e 1 ) . A p p a r e n t l y Κ and v e r a t r i d i n e have d i f f e r e n t mechanisms f o r stimulating calcium uptake. High concentrations of e x t r a c e l l u l a r Κ reduce t h e normally l a r g e g r a d i e n t between intraand e x t r a c e l l u l a r Κ levels and cause membrane depolarization. In contrast, v e r a t r i d i n e prevents i n a c t i v a t i o n o f Na c h a n n e l s , t h u s a l l o w i n g e x c e s s i v e a c c u m u l a t i o n o f Na intracellularly, and t h i s , i n turn, results i n membrane depolarization. I n e i t h e r c a s e Ca u p t a k e i s s t i m u l a t e d by t h e


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depolarization. Since t h e e f f e c t o f v e r a t r i d i n e i s Nad e p e n d e n t , i t i s i n h i b i t e d by t e t r o d o t o x i n , a s p e c i f i c b l o c k e r o f Na c h a n n e l s (9). I n c o n t r a s t , t h e a c t i o n o f Κ i s Nai n d e p e n d e n t and i s u n a f f e c t e d by t e t r o d o t o x i n . O b v i o u s l y , Mn, w h i c h a c t s p r i m a r i l y by o c c l u d i n g Ca c h a n n e l s ( 1 0 ) , has a n e q u i v a l e n t e f f e c t on K- and v e r a t r i d i n e - i n d u c e d Ca u p t a k e .


E f f e c t of Phenytoin

and O t h e r H y d a n t o i n s

Phenytoin a l s o a f f e c t s c a l c i u m uptake i n synaptosomes. S i m i l a r t o Mn, i t i n h i b i t s t h e a c t i o n o f b o t h v e r a t r i d i n e and K, b u t l i k e t e t r o d o t o x i n i t i s much more e f f e c t i v e a g a i n s t v e r a t r i d i n e ( F i g u r e 2 ) . S t i m u l a t e d Ca u p t a k e p r o d u c e d a t a l l c o n c e n t r a t i o n s o f Κ between 15 and 64 mM i s i n h i b i t e d 2 0 % by 0.1 mM phenytoin, and t h i s i s u n a f f e c t e d by t e t r o d o t o x i n . Examination of the dose-related effect of phenytoin on stimulated Ca u p t a k e p r o d u c e d by 23 and 64 mM Κ r e v e a l s i d e n t i c a l p r o p o r t i o n a l i n h i b i t i o n of both. Thus, i n h i b i t i o n o f K-induced Ca uptake by phenytoin i s independent of Κ concentration. I n c o n t r a s t , t h e r e a p p e a r s t o be a c o m p e t i t i v e i n t e r a c t i o n between v e r a t r i d i n e and p h e n y t o i n . Phenytoin has a much g r e a t e r i n h i b i t o r y e f f e c t , p r o p o r t i o n a l l y , on Ca u p t a k e stimulated by l o w c o n c e n t r a t i o n s of v e r a t r i d i n e than that produced by h i g h e r concentrations. For example, 35 μΜ p h e n y t o i n c a u s e d 5 0 % i n h i b i t i o n o f Ca u p t a k e p r o d u c e d by 5 μΜ veratridine, but ~ 225 μΜ p h e n y t o i n i s required f o r 50% i n h i b i t i o n o f t h e Ca u p t a k e p r o d u c e d by 100 μΜ v e r a t r i d i n e . Thus, phenytoin appears to inhibit K-induced and veratridine-induced calcium u p t a k e by d i f f e r e n t m e c h a n i s m s . P r e s e n t d a t a d e m o n s t r a t e t h a t p h e n y t o i n h a s an a c t i o n s i m i l a r , but n o t i d e n t i c a l , t o t h a t o f t e t r o d o t o x i n , as w e l l as an a c t i o n l i k e , b u t a l s o n o t i d e n t i c a l , t o t h a t o f Mn. Other i n v e s t i g a t o r s have r e p o r t e d t h a t p h e n y t o i n b l o c k s Na c h a n n e l s i n l o b s t e r n e r v e and s q u i d g i a n t a x o n ( 1 1 - 1 3 ) and t h i s i s n o t a Ca-dependent process. The p r e s e n t data demonstrate that p h e n y t o i n i s a b l e t o b l o c k K - s t i m u l a t e d Ca u p t a k e , and t h i s i s unaffected by t e t r o d o t o x i n , i n d i c a t i n g t h a t t h i s e f f e c t i s i n d e p e n d e n t o f Na. We t h i n k t h a t a l l o f t h e d a t a together s u g g e s t t h a t p h e n y t o i n c a n i n h i b i t b o t h Na and Ca c o n d u c t a n c e s i n n e r v o u s t i s s u e and t h a t t h e s e a r e s e p a r a t e and i n d e p e n d e n t processes. The present results also indicate that Na c o n d u c t a n c e may be more s e n s i t i v e t o t h e i n h i b i t o r y a c t i o n o f p h e n y t o i n , b u t more r e s e a r c h w i l l be n e c e s s a r y t o p r o v e t h i s contention. The e f f e c t s o f p h e n y t o i n on K- and v e r a t r i d i n e - i n d u c e d Ca u p t a k e have been compared w i t h t h o s e o f o t h e r h y d a n t o i n s ( T a b l e 1). These i n c l u d e t h e m a j o r in_ v i v o m e t a b o l i t e o f p h e n y t o i n , hydroxyphenyl-phenylhydantoin (HPPH); mephenytoin, another antiepileptic hydantoin; i t s major m e t a b o l i t e , 5-ethyl-5-


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Figure. 1. Effect of tetrodotoxin (left) and Mn (right) on stimulated Ca uptake by rat brain synaptosomes. Uptake of Ca was stimulated by exposing synapto somal suspensions to 5 μΜ veratridine (%) for 5 min or to 64 mM K+ (O) for 15 s in the absence or presence of the indicated concentrations of tetrodotoxin or MnCl . Values are expressed as percentage of control (absence of tetrodotoxin and Mn) stimulation (4.1 ± 0.7 μΐηοΐ Ca accumulated/g prot). Each point and vertical line represents the mean and SEM, respectively, of triplicate samples. 2+

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CONCENTRATION OF PHENYTOIN (M) Figure 2. Effect of phenytoin concentration on K- and veratridine-stimulated Ca uptake in rat brain synaptosomes. Synaptosomal uptake of Ca was stimulated by exposure of the tissue to 64 mM K (O) for 15 s or 5 μΜ veratridine (%) for 5 min. In the absence of phenytoin control, stimulation was 4.7 ± 0.3 and 6.1 ± 0.8 μmol Ca/g prot for K and veratridine, respectively. Each symbol and vertical line represents the mean and SEM, respectively, of 6 samples. 45

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In Calcium Regulation by Calcium Antagonists; Rahwan, Ralf G., et al.; Washington, D.C. 20036 ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


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p h e n y l h y d a n t o i n ; and h y d a n t o i n i t s e l f . A l l compounds e x c e p t h y d a n t o i n i n h i b i t b o t h K- and v e r a t r i d i n e - i n d u c e d Ca u p t a k e a t concentrations less than 1 mM ( t h e h i g h e s t dose tested). However, HPPH, m e p h e n y t o i n and i t s d e r o e t h y l a t e d d e r i v a t i v e a r e all l e s s potent t h a n p h e n y t o i n by an o r d e r o f m a g n i t u d e . S i m i l a r t o p h e n y t o i n , t h e o t h e r e f f e c t i v e h y d a n t o i n s a r e more active against veratridine than against K-stimulated Ca a c c u m u l a t i o n , a l t h o u g h none e x h i b i t as much s e l e c t i v i t y as phenytoin. T h u s , t h e i n h i b i t o r y a c t i o n o f p h e n y t o i n on i o n i c p e r m e a b i l i t y i s s i g n i f i c a n t l y a l t e r e d by m o d i f i c a t i o n o f i t s molecular structure. The a d d i t i o n o f a h y d r o x y l g r o u p t o one phenyl r i n g or replacement o f a p h e n y l g r o u p w i t h an a l k y l g r o u p d i m i n i s h e s p o t e n c y and seems t o d e c r e a s e t h e r e l a t i v e l y greater inhibitory action against Na-dependent Ca uptake. These c h a n g e s i n e f f e c t s may s i m p l y be due t o l o w e r lipid s o l u b i l i t y of the o t h e r h y d a n t o i n d e r i v a t i v e s . Regardless, the results suggest that phenytoin has actions which are q u a n t i t a t i v e l y , and p e r h a p s q u a l i t a t i v e l y , d i f f e r e n t f r o m t h o s e of o t h e r a n t i c o n v u l s a n t h y d a n t o i n s .

Table

1

I n h i b i t o r y E f f e c t s of Hydantoins on K- and V e r a t r i d i n e - S t i m u l a t e d C a l c i u m U p t a k e i n Synaptosomes

Drug

Drug C o n c e n t r a t i o n (μιη) P r o d u c i n g I n h i b i t i o n o f Ca U p t a k e Veratridine Κ

Phenytoin Hyd

Mephenytoin 5-Ethyl-5-phenylhydantoin Hydantoin

E f f e c t of Other We

350

210

900

800

1200

roxypheny1-

phenylhydantoin

found

35

50%

Antiepileptic

450 10,000

1600 10,000

Drugs

have a l s o t e s t e d s e v e r a l o t h e r a n t i c o n v u l s a n t d r u g s that carbamazepine, phénobarbital, lidocaine,


and and


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Drugs

d i a z e p a m i n h i b i t s t i m u l a t e d Ca u p t a k e i n s y n a p t o s o m e s ( T a b l e 2). E t h o s u x i r a i d e and v a l p r o i c a c i d , h o w e v e r , h a v e no e f f e c t e x e p t a t a c o n c e n t r a t i o n o f 10 mM, a n d e v e n a t t h i s extremely h i g h c o n c e n t r a t i o n they produce o n l y very l i t t l e inhibition. Phénobarbital i s c l e a r l y l e s s p o t e n t t h a n p h e n y t o i n by a n o r d e r of magnitude o r g r e a t e r , b u t carbamazepine, l i d o c a i n e and diazepam a r e n e a r l y equipotent with phenytoin. Similar to phenytoin, carbamazepine and l i d o c a i n e b l o c k e d v e r a t r i d i n e s t i m u l a t e d Ca u p t a k e much b e t t e r t h a n K - s t i m u l a t e d uptake. Phénobarbital a n d d i a z e p a m have l i t t l e o r no d i f f e r e n t i a l e f f e c t on t h e two d e p o l a r i z i n g a g e n t s , however. T h u s , w i t h t h e e x c e p t i o n o f e t h o s u x i m i d e and v a l p r o i c a c i d , a l l a n t i e p i l e p t i c drugs tested are effective. However, phénobarbital i s c o n s i d e r a b l y l e s s p o t e n t , a n d b o t h phénobarbital and d i a z e p a m do n o t a p p e a r t o have a n y s l e c t i v e e f f e c t a g a i n s t v e r a t r i d i n e i d u c e d Ca u p t a k e .

Table 2 I n h i b i t o r y E f f e c t s o f Some A n t i c o n v u l s a n t on K- a n d V e r a t r i d i n e S t i m u l a t e d C a l c i u m U p t a k e i n Synaptosomes

Drug

Phenytoin Carbamazepein

Drug C o n c e n t r a t i o n (ym) P r o d u c i n g 5 0 % I n h i b i t i o n o f Ca U p t a k e Κ Veratridine 35

350

100

1800

10

Lidocaine Phénobarbital

1350 65

Diazepam

Drugs

> 1000 4500 100

Ethosuximide

>10,000

>10,000

Valproic

>10,000

>10,000

Acid

Thus, o n l y c a r b a m a z e p i n e a n d l i d o c a i n e have a c t i o n s v e r y s i m i l a r t o those o f phenytoin. L i d o c a i n e , a s w e l l a s most other local anesthetics, inhibits Na c o n d u c t a n c e i n n e r v e f i b e r s ( 1 4 , 1 5 ) . There a r e a l s o l i m i t e d data i n d i c a t i n g t h a t carbamazepine i s capable of blocking Na p e r m e a b i l i t y i n M y x i c o l a g i a n t axons ( 1 6 ) . These d a t a , i n c o n j u n c t i o n w i t h t h e



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CALCIUM REGULATION BY CALCIUM

ANTAGONISTS

present results, suggest that carbamazepine and l i d o c a i n e i n h i b i t both Na and Ca conductances i n nervous t i s s u e s s i m i l a r to phenytoin. The mechanisms r e s p o n s i b l e for inhibition of ionic conductances exhibitedby the s e v e r a l drugs described above a r e poorly understood a t present. I t has been proposed that l o c a l a n e s t h e t i c s (e.g., l i d o c a i n e ) s e l e c t i v e l y block Na conductance by combining with s p e c i f i c receptor s i t e s i n or near the Na channel (14,17). P o s s i b l y phenytoin and carbamazepine a l s o a c t at s i t e s on or near Na channels, and these two drugs may have specific and s e l e c t i v e a c t i o n on Na conductance, perhaps s i m i l a r to that of l i d o c a i n e . Whether these drugs and others examined i n t h i s study block Ca conductance by a d i r e c t or i n d i r e c t process i s d i f f i c u l t to a s c e r t a i n . We are impressed, however, with the f a c t that the more l i p i d s o l u b l e agents (e.g., diazepam) are more effective inhibitors of Naindependent Ca uptake than the more water s o l u b l e compounds (^•g-, phénobarbital). Perhaps Na-independent i n h i b i t i o n of Ca conductance r e s u l t s from a drug e n t e r i n g c e l l u l a r membranes i n s u f f i c i e n t q u a n t i t y to p h y s i c a l l y d i s t o r t t h e i r o r g a n i z a t i o n and by t h i s means modify the s t r u c t u r e and f u n c t i o n of i o n i c channels. We suggest that t h i s mechanism may best e x p l a i n i n h i b i t i o n of K-induced Ca uptake observed with phenytoin, l i d o c a i n e and carbamazepine and may a l s o e x p l a i n the a c t i o n s of diazepam and phénobarbital on both K- and v e r a t r i d i n e - i n d u c e d Ca uptake. Role of Calcium Mechanisms

and

Sodium

Antigonism

in

Anticonvulsant

An i s s u e worthy of c o n s i d e r a t i o n i s the question of whether the a n t i e p i l e p t i c or other c l i n i c a l e f f e c t s of any of the drugs examined here are wholly or p a r t i a l l y a r e s u l t of t h e i r i n h i b i t i o n of Ca and/or Na movement across c e l l u l a r membranes. Although there are s e v e r a l f a c t o r s that could be considered when attempting to answer t h i s question, one of the more important i s drug c o n c e n t r a t i o n . Obviously, i f an a c t i o n of a drug i s r e l a t e d to i t s c l i n i c a l e f f e c t , both would be expected to occur at the same or n e a r l y the same drug concentration. Therapeutic concentrations of a n t i e p i l e p t i c drugs (18) are l i s t e d i n Table 3. Only phenytoin, carbamazepine, and perhaps lidocaine inhibit veratridineinduced Ca accumulation a t concentrations which approximate their "therapeutic l e v e l s . " K-induced Ca uptake i s a l s o i n h i b i t e d a small amount (10-20%) by "therapeutic l e v e l s " of phenytoin. A l l of the other a c t i o n s observed i n t h i s study occur a t drug concentrations which are 1-2 or more orders of magnitude higher than those u s u a l l y achieved c l i n i c a l l y . Thus, we conclude that i n h i b i t i o n of Na and/or Ca uptake could be a


8.

FERRENDELLi

Antiepileptic

Drugs

151

mechanism of a c t i o n underlying the c l i n i c a l e f f e c t s of phenytoin, carbamazepine and l i d o c a i n e , but t h i s process probably i s not involved i n the c l i n i c a l e f f e c t s of the other drugs examined i n t h i s study.

Table 3


C l i n i c a l l y E f f e c t i v e Blood Levels of Some A n t i e p i l e p t i c Drugs

Drugs

Therapeutic

Phenytoin

40 - 80

Carbamazepine

20 - 50

Phénobarbital

60 - 160

Blood Level (μπι)

1

Diazepam Ethosuximide

350 -• 700

Valproid

350 -• 650

Acoid

Lidocaine

10 -• 20

Furthermore, we think, that one may a l s o conclude that the c l i n i c a l e f f e c t s of phenytoin, carbamazepine and l i d o c a i n e are most l i k e l y due to t h e i r i n h i b i t o r y a c t i o n on Na uptake rather than a primary a c t i o n on Ca conductance. This i s based on the f i n d i n g that much lower concentrations of a l l three drugs are needed to i n h i b i t v e r a t r i d i n e - s t i m u l a t e d ( i . e . , Na-dependent) Ca uptake than are required to i n h i b i t K-stiraulated (Naindependent) Ca uptake. This does not n e c e s s a r i l y imply that an a l t e r a t i o n of Ca conductances i s not involved i n the c l i n i c a l e f f e c t s of the above drugs. In the CNS, i n s i t u , Ca uptake i s stimulated by c e l l u l a r d e p o l a r i z a t i o n which r e s u l t s from augmented Na i n f l u x . Obviously, impairment of Na i n f l u x by a drug would secondarily diminish Ca uptake. Also, a t l e a s t i n the case of phenytoin, d i r e c t i n h i b i t i o n of Ca uptake may have a r o l e i n i t s c l i n i c a l e f f e c t . Acknowledgment Supported, i n p a r t , by USPdS Grant NS-14834



152

CALCIUM REGULATION BY CALCIUM ANTAGONISTS

Literature Cited 1. Sohn, R. S.; Ferrendelli, J. A. J. Pharmacol. Exp. Ther. 1973, 185, 272-275. 2. Sohn, R. S.; Ferrendelli, J. A. Arch. Neurol. 1976, 33, 626-629. 3. Ferrendelli, J. Α.; Daniels-McQueen, S. J. Pharmacol. Exp. Ther. 1982, 220, 29-34. 4. Blaustein, M. P. J. Physiol. 1975, 247, 627-655. 5. Blaustein, M. P.; Ector, A. C. Mol. Pharmacol. 1975, 11, 369-378. 6. Blaustein, M. P.; Ector, A.C. Biochim. Biophys. 1976, 419, 295-308. 7. Blaustein, M. P.; Goldring, J. M. J. Physiol. 1975, 247, 589-615. 8. Krueger, Β. K.; Ratzlaff, R. W.; Strichartz, G. R.; Blaustein, M. P. J. Memb. Biol. 1979, 50, 287-310. 9. Narahashi, T. Physiol. Rev. 1974, 54, 813-888. 10. Nachshen, D. Α.; Blaustein, M. P. J. Gen. Physiol. 1980, 76, 709-728., 11. Lipicky, R. J.; Gilbert, D. L.; Stillman, I. M. Proc. Natl. Acad. Sci. USA 1972, 69, 1758-1760. 12. Pincus, J. H. Arch. Neurol. 1972, 26, 4-10. 13. Perry, J. G.; McKinney, L.; Deweer, P. Nature 1978, 272, 271-273. 14. Strichartz, G. R. J. Gen. Physiol. 1973, 62, 37-57. 15. Ritchie, J. M. Br. J. Pharmacol. 1975, 74, 191-198. 16. Schant, C. L.; Davis, F. Α.; Marder, V. J. Pharmacol. Expt. Ther. 1974, 189, 538-543. 17. Hille, B. J. Gen. Physiol. 1977, 69, 497-515. 18. Kutt, H.; McDowell, F. "Clinical Neuropathology"; Churchill Livingstone: New York, 1979, pp. 12-53. RECEIVED June 1, 1982.


Calcium Antagonism and Antiepileptic Drugs - American Chemical

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