++modes of Action of Antihelmintic Drugs

 

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Modes of action of anthelmintic drugs  Article  in  The Veterinary Journal · August 1997 DOI: 10.1016/S1090-0233(05)80005-X · Source: PubMed

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The I eteHnaU.flmrna11997, 154, 11-34

Review M od es of R J

c t io io n o f

n t h e lm i n ti c D r u g s

MARTIN

De pa,/m en/ o / l ,e ,li ,i, al Vete, i,m,y .Sc .Scienc iences. es. R. CDOS CDOS..V.S., Su,n,,, Su,n,,,e,hall. e,hall. Universit Universityy of Edinbu,gh, Edinburgh Etq9 I QH, UK

SUMMARY

Modes of action of anthelmintic drugs are described. Some anthelmintic drugs act rapidly and selectively on neuronmscular transmission of nematodes. Levamisole, pyrantel and morantel are agonists at nicotinic acetylcholine receptors of nematode muscle and cause spastic paralysis. Dichlorvos and haloxon are organophosphorus cholinesterase antagonists. Piperazine is a GABA (T-amino-bu~ric acid) agonist at receptors on nematode muscles and causes flaccid paralysis. The avermectins increase the opening of glutanmte-gated chh)ride (GltlC1) channels and produce paralysis of phmTngeal pumping. Praziquantel has a selective selective efl efl ect on the teg umen t o f trematodes and increa increases ses permeabil ity of calcium. calcium. Ot her anthehnintics have a biochemical mode of action. The benzimidazole drugs bind selectively to ~-tubulin of nematodes, cestodes and fluke, and inhibit nficrotubule formation. The salicylanilides: rafoxanide, oxych)zanide, brotianide and closantel and the substituted phenol, nitroxynil, are proton ionophores. Clorsuhm is a selective antagonist of fluke phosphoglycerate kinase and mutase. Diethylcarbamazine blocks host, and possibly parasite, enzymes involved in arachidonic acid metabolism, and enhances the innate, nonspecific immune system. Kx-~WOnl)S: Mod e o f action ; an the hni nt ics ; levamisole; dichlorv os; pi pera zine ; av ermec tins ; pra ziq uan tel; benzimidazoles; sali salicyla cylanili nilides; des; clorsulon; diethylcarbamazine.

INTRODUCTION

Parasitic nematodes affect animals and man causing considerable suffering and poor growth. Effective anthehnintic drugs, used to treat and control these infestations, must have selective toxic effects on these parasites. Unfortunately with the increased use of these compounds, anthelmintic resistance has appeared and increa sed in fl-equency (Prichard, 1994 1994). ). If re resi sist st-ance to a particular anthehnintic has occurred, it is likely that another anthelmintic with the same mode of action will also be ineffective although other anthehnintics with another mode of action, may still be effective. Clearly then, it is important to have have an an unders tandin g of the the mode of actio action n of anthehnintics in order to inform the selection of

N I C O T I N IC

AGON ISTS

Levamisole, lmtamisole, pyrantel, m orantel, oxantel, bephenium and thenium Fig. 1 shows the chemical structures of nicotinic anthelmintics. There are the imidazothiazoles (levamisole and butamisole); the tetrahydropyrimidines (pyrantel, morantel and oxantel); the quaternatT ernat T ammonium salts (bephenium and theniuna) and tile pyrimidines (methyridine). Thes e co mp ou nd s act selectively as agonists at syn syn-aptic and extrasynaptic nicotinic acetTlcholine receptors on nematode muscle cells (Fig. 2) and produce contraction and spastic paralysis. The electrophysiological effects of levamisole, pyrantel, morantel and oxantel have been studied i n greatest detail.

effective therapeutic agents. This rexqew describes modes of action of anth elmin tic drugs (Table I). I). 1 190-0233/t)7/04 1011-24/S 12.00 /0

© 1997 Bai Bailli6 lli6re re Tinda ll

 

12

T H E V E H . : R IN IN . .\.\ R Y . I OL'R N A I . . 154, I

Table I. S u m m a r y ta t a b le l e o f t h e m o d e s o f a c t i o n o f a n t h e l m i n ti ti c d r u g s

(;e,eric drueff n a m e Nicotinic agonists

Iqxam/de,~

,w,me ( .

Stl(ingid P;u alct l ( :anlll)ar

11;llOXOll

Mulitwttrma

nlcthvridinc

dichhwvos

GABA agonist

pipura/hic

End.rid.

Giu CI p o ten tia to rs

ivt l+lllt C lill al)alllcclill d~WalllCClill

[ V ( I II II R C

inoxidcciin niill)cinvcin l)

(

C a l c i u m p e r m e a b i l it it y i n c r e a s e

praziqu,in tel

l)l~mcit

[~-tubuli [~-t ubulin n bind ing

thial)cnda]acetyltylchol ine (Harro w Grati on, 19 1985 85). ). In addition to effects of tile anthehnintics on the membrane conductance of the muscle, Harrow and Gration (1985) described the conductance dose-response curves for pyrantel and morantel as being 'bell shaped'. The effect of this this concentration-effect relationship is that the conductance-response increases then decreases as the concentration of the anthelmintics rises. One explanation tor this pheno men a is that that of open chann el block (Col quho un Sakmann, 19 1985 85)) by the anthelmintic. Levamisole, pyrantel, morantel and oxantel are large organic cations, and could enter the nicotinic ion-channel from the outside and tl tl-y -y to pass th ro ug h the cha nne l like Na + or K+ ions but produce the block at the narrow region of the channel, the selectivity filter. This block

same nicotinic receptors, and the relative potency of the anthehnintics in bath application exper-

would be voltage-sensitive and increase with h y p e r p o l a r i z a t i o n of the membrane and c o n c e n

 

14

T H E V E T E R I NA NA R Y . J O U R N A L

154, 1

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Syncylium

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1 mm

Ventral nerve cord

b)

Posterior

Anterior

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YY

Y

V

Y

Dorsal nerve

Y Y

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k 2~ k o

Y Y Y Y Y

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v

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Ventral nerve cord

Y V T

F ig i g . 2 . D i a g r a m s o f t il i l e n e u r o n m s c u l a r o r g a n i z a t i o n o f n e m a t o d e s o m a t i c m u s c l e . ( a ) D i a g r a m o f a s ( m m l ic i c m u s c l e c el el l s h o w i n g : t h e c o n t r a c t i l e s p i n d l e r e g i o n ; t i le l e b a l l o o n - s h a p e d b a g t h a t c o n t a i n s t il i l e n u c l e u s a n d g l y c o g e n g r a n u l e s ; t i le le a r m w h i c h i s a p r o c e s s o f t i le l e m u s c l e a n d r e a c h e s t o o n e o f t il i l e n e r v e c o r d s w h e r e i , d i v i d e s i n t o t ] n g e r s I h a l I ( ) ln l n l al al l e l e c t r i c a l l y - c o u p l e d c o m p l e x w i t h t h e f i n g e r s o f a d j a c e n t m u s c l e c e l l s a n d c o l l e c t i v e h ' i s k n o w n a s t h e s v n c v ti ti t m l . T h e m u s c l e c e l l p o s s e s s e s s y n a p t i c n i c o t i n i c a c e t y l c h o l i n e r e c e p t o r s , a n d s y n a p t i c G A B A r e c e p t o r s a t t il i l e s v n c v t ia ia l r e g i o n a n d e x t r a s y n a p t i c a c e t y l c h o l i n e a n d G ,M , M I A r e c e p t o r s o v e r t il i l e su s u r f a ce c e o f t h e m u s c l e. e. ( b ) D i a g r a m o f t h e d o r s a l a n d v e n t r a l n e r v e c o r d s h o w i n g t h e c e ll ll r e p r e s e n t e d i n a s e g m e n t . A l l t il i l e ce c e ll l l b o d i e s o f t il i l e m o t o r n e t t r o n e s a r e c o n t a i n e d i n t il il e v e n t r a l n e r v e co co r d . E a c h s e g m e n t h a s t h r e e r i g h t - h a n d c o m m i s s u r e s a n d o n e l e f t - h a n d c o m m i s s u r e . E a c h c o m m i s s u r e i s m a d e u p o f o n e o r t wo w o a x o n s o r d e n d r i t e s o f t il i l e m o t o r n e u r o n e s t h a t p as a s s r o u n d t h e b o d y t o c o n n e c t t il il e v e n t r a l a n d d o r s a l n e r v e c o rd r d . W i t h i n e a c h s e g m e n t t h e r e a r e 1 1 m o t o r n e r o - o n e s th t h a t a r e d i v id i d e d i n t o s e v e n a n a t o m i c a l t y p es es ( D E I , D E 2 , D E 3 : d o r sa s a l e xc x c itit at at o~ o~ 3. 3. ' m o t o r n e u r o n e s . D I : d o r s a l i n h i b i t o r y m o t o r n e u r o n e s . V I : v e n t r a l i n h i b i t o r y m o t o r n e u r o n e . VI V 2 : v e n t r a l e x c it i t a to t o c v n t o t o r n e u r o n e s . T h e r e m a i n i n g a x o n s i n t h e v e n t r a l n e lw lw e c o r d a r e i n t e r s e g m e n t a l n e u r o n e s . T i l e e x ci c i t a to t o r y m o t o r n e u r o n e s a r e c h o l i n e r g i c a n d t il i l e i n h i b i t o r y m o t o r n e u r o n e s a r e G A B A e r g i c. c . ( c ) D i a g r m n o f a c r o ss ss s e c t i o n o f t h e b o d y j u s t c a u d a l t o t h e p h a u , n g e a l m u s c l e . I t sh s h o w s t h e r e l a t iv i v e l o c a t i o n s o f ti t i l e n e r v e c o r d s , l a t e r a l l i n es es , g u t and muscle cells.

Single channel currents activated by nicotinic anthelmintics

prepar ation (Robertson Martin, 19 1993 93)) using the patch-clamp technique. The ion-chalmel currents activated by low levamisole concentrations were shown to cart3 cart3 cations and to have similar kinetics to acetylcholine-activated channels. The lev levami ami-sole activated channels have a mean open time of 1.34 ms and a conductance in the range 20-45 pS.

Initially, levamisole-activated channel currents [Fig. 3(a)] were recorded fi'om the muscle vesicle

At higher concentrations of levamisole, a flickering open channel block that increases on hyper-

tration of the anthelmintic. This property of producing open channel block has been established using single-channel recording techniques (Robe rtson Martin, 1993 1993). ).

 

MODES OF ACTION OF ANTHELM INTI( DRUGS

15

p o l a r i z a t i o n i s o b s e l - v e d [ F ig ig . 3 ( b ) ] . A t - 5 0 m V t h e d i s s o c ia i a t io io n c o n s t a n t f o r t h e c h a n n e l b l o c k w a s 1 2 3 ~ ,x ,x l.l. I n a d d i t i o n t o t h e f l i c k e r i n g b l o c k , c l u s t e r s o f o p e n i n g s w e r e a ls ls o o b s e r v e d a t h i g h l e v a m is is o l e c o n c e n t r a t i o n s w h e r e o p e n i n g s w e r e s e p a r a t e d b y l o n g ( s e c o n d s ) c l o s e d t im i m e s : th th i s c h l s t e r i n g b e h a v i o u r i s s i m i l ar ar t o t h a t a s s t u n e d t o be desensitization in vertebrates but was more

w i th t h o x a n t e l , o c c u p y i n g a n i n t e r m e d i a t e p o s i ti ti o n b e t w e e n m o r a n t e l a n d o x a n t e l . T h e l ea ea s t p o t e n t a g o n i s t i n A s c a r i s is o x a n t e l w h i c h p r o d u c e s t h e l o w e s t p r o b a b i l i tT tT o f c h a n n e l o p e n i n g e v e n a t h i g h c o n c e n t r a t i o n s ( D a l e & M a r t i n , 1 9 9 5 ) . h a t e rre s ti t i n g ly ly , o x a n t e l is n o t e f f e c t i v e t h e r a p e u t i c a l l y a g a i n s t a s c a r i a s is is b u t is u s e d i n s t e a d t o t r e a t 7) ichuris i n f e c t i o n s . T h e e f f ic ic a c y o f o x a n t e l a g a i n s t

v o l ta t a g e -s - s e n si s i ti ti v e a n d m o r e p r o m i n e n t a t h y p e r p o l a r i z e d p o t e n t i a l s i n Ascaris. P y r a n t e l - a c t i v a t e d c h a n n e l s [ Fi F i g. g . 3 ( c ) ] h a v e a ls ls o been recorde d u s in i n g t h e s a m e p r e p a r a t io io n ( R o b e r t s o n el al., 1 9 9 2 ) . P v r a n t e l - a c t i v a t e d c h a n n e l s h o w e d a t l ea ea s t t w o d i s t i n g u i s h a b l e c o n d u c t a n c e l e v el e l s: s : t h e m a i n c o n d n c t a n c e l e ve ve l w a s n e a r 4 0 p S a n d t h e s m a l l e r c o n d u c t a n c e l ev e v e l w as as n e a r ' 2 2 p S , s u g g e s ti ti n g t h e p r e s e n c e o f m o r e t h a n o n e t y p e o f n i co co t i n i c r e c e p t o r i n t h e m e m b r a n e . A g a i n, n, t h e c h a n n e l s o p e n e d b y p y r a n t e l w e r e shown to be pernm able to mono valent cations and channel-block occurred at hyperpolarized potent i a ls ls . T h e c h a n n e l b l o c k o c c u r r e d m o r e r e a d i ly ly

7 ) i c h u d s b u t n o t a g a i n s t A s c a H s m a y b e d u e t o d i fff e r e n c e s in i n t h e n i c o t i n i c r e c e p t o r s o f t h e tw tw o s p e ci c i e s o f n e m a t o d e : o x a n t e l m a y b e e f f e c ti ti v e a n d p r o d u c e o p e n i n g o f t h e TtJchuris n i c o t i n i c a c e t y l c h o l i n e r e c e p t o r b u t n o t s o ef e f f ec e c t iv iv e o n t h e A s c a r i s r e c e p to t o r . T h e c o n c e n t r a t i o n s o f o x a n te te l a n d p y r a n t e l a l o n g t h e i n t e s t i n e m a y al a l so s o b e a fa fa c t o r a f f e c t i n g e f f i c a c ie ie s o f t h e d r u g s .

w i t h p y r a n t e l t h a n w i t h le l e v a m i s o l e a s s h o w n b y th th e t a c t t h a t t h e d i s s o c i a t i o n c o n s t a n t , /x ] ~ , f o r l e v a m i s o l e w a s la la i g h e r t h a n t h a t o f p y r a n t e l ( l e v a m i s o l e ~ a t - 5 0 n t V 1 2 3 ~ tx tx l; l; p y r a n t e l K]~ a t - 5 0 n a V 37 btxl). T a l ) l e II s u m m a r i z e s t h e c h a n n e l I ) l o c k i n g p r o p e r t i e s o f l e v am am i s o l e a n d p y r a n t e l a n d , in addition, mora ntel and oxantel. Som e general p o i n t s m a y b e m a d e b y e x a m i n i n g T a b l e I I. I. It It c a n be seen that all the nicotinic anthehnintics prod u c e o p e n c h a n n e l - b l o c k , a f o r m o f s e lf lf a n t a g o n isnt, and that levamisole is the least potent at b l o c k i n g i t s o w n c h a n n e l . T h e s i g n it i t i ca ca n c e o f t h e o p e n c h a n n e l b l o c k n t a y r e l a t e t o t h e a b il i l it it y o f s o m e n e m a t o d e s t o r e s is is t t h e e f f e c t s o f n i c o t i n i c anthehninitics: chan nel block may occur at such l ow ow a n t h e l m i n t i c c o n c e n t r a t i o n s t h a t n o r m a l c o n c e n t r a t i o n s o f a n t h e l m i n t i c a r e i n e f f ec e c t iv iv e . I n A s c m i s , t h e c h a n n e l - b l o c k i n g a b il i l it it y o f p y r a n t e l i s g r e a t e r t h a n l e v a m i s o l e, e, b u t t h e g r e a t e s t c h a n n e l - b l o c k is is p r o d u c e d b y m o r a n t e l

tein-coupled m uscarinic receptors. An action in nematodes at acetylcholine receptors analogous to vertebrate muscarinic receptors, mo dulating voltage-sensitive ion channels has yet to be fully reported. Th ere is biochem ical exidence for the presenc e o f 'm 'm u s c a r i n i c ' r e c e p t o r s i n A s c ar is m u s c l e : ( 1 ) D o n a h u e et aL ( 1 9 8 2 ) h a v e o b s e v v e d t h a t effects of cho linerg ic stimulation inchtdes i n c r e a s e s i n l e v e ls l s o f c y c li l i c -A -A M P ; ( 2) 2) A r e v a l o a n d S a z ( 1 9 9 2 ) h a v e o b s e r v e d t h a t a c e t y l c h o l i n e i n c r e a s e s l ev e v e ls l s o f p h o s p h o D , lc h o l i n e , 1 , 2 - d i a c y lg l g l y c e r id id e s a n d p h o s p h a t i d i c a c id id , a n d d e m o n s t r a t e d t h e p r e s e n c e o f p h o s p h o l i p a s e C a c t i v i tT tT . D o n a h u e et al. ( 1 9 8 2 ) a n d A r e v a l o a n d S a z ( 1 9 9 2 ) d i d n o t d is is t i ng n g u i s h b e t w e e n ' m u s c a r i n i c ' o r ' n i c o t i n ic ic ' cholinergic receptors. P r e v i o u s s t u d ie i e s o n n e m a t o d e s h a v e s h ow ow n t h a t r e s i s t a n c e to t o n i c o t i n i c a n t h e l m i n t i c s m a y ta ta k e t w o f o r m s : ( 1 ) T h e s e l e c t i o n o f g e n e t i c a l l y r e s i st st a n t

N o n - n i c o t i n i c o r m u s c a r i n i c c h o l i n e r ~ c r ec ec ep ep to t o r~ r~ i n n e m a t o d e s a n d r e s is i s t a n ce c e to to a n t h e l m i n t i c s I n a n u m b e r o f v e r t e b r a t e p r e p a r a t i o n s , a c e ty t y llc h o l i n e i s a b l e t o a l te t e r t h e p r o b a b i l i t y of of o p e n i n g o f v o l t a g e - d e p e n d e n t c h a n n e l s b y a c t in in g v i a G - p r o -

Table II V o l t a g e s e n s i ti t i v i ty ty o f d i s s o c i a t i o n c o n s t a n t s o f o p e n c h a n n e l b l o c k b y t h e n i c o t i n i c a n t h e l m i n t i c s

Mem brane -50 mV -75 mV

Voltage-sensitivlty of h]~

I¢3 ¢333 l.evamisole

2KI, l5,rantel

Kl~~ Mo rantel Kl

KR Oxa ntel

1 23 23 I.tXJ I.tXJ 4 6 IJ IJM M

3 7 IJ.Xl Xl 20 I.t~l e-fold eve D' 40 mV

12 p.x p.xtt 1 ~ xl

18. 5 I.tM 7.5 law

e-fold every 20 mV

e-fbld every 22 mV

e-fold ever ever), ), 29 mV

/ ~ i s t h e d i s s o c i a t io io n c o n s t a n t : t h e l o w e r t h e c o n c e n t r a t i o n o f t hi hi s c o n s t a n t t h e m o r e p o t e n t i t is is . A t t h e c o n c e n t r a t i o n o f t h e K B th th e c h a n n e l i s b l o c k e d f o r 5 0 % o f i ts ts o p e n t i m e s o ti ti l e r e s p o n s e w o u l d b e r e d u c e d by a half.

 

16

T H E V E T E R I N A R Y J O U R N A L . 1 5 4, 4, 1 ( a }L e v a m i s o l e 15

10

0

1 pA L 0

5

10

15

20 m s

(b~

............

i

...... ... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ....... i

A 3 ~ m

~~

...... ... ...

C 0

( c) c) P y r a n t e l C 15O 10-

C

0-

O 0

5

10

15

20 m s

F i g . 3 . P a t c h - c l a m p r e c o r d s o f s i l ag a g l e - c h a n n e l c u r r e n t s a c t i v a t e d b y l e v a m i s o l e . T h e p a t c h - c l a m p t e c h n i q u e a l lo lo w s t h e a c t iv i v i t ' o f s i n g l e i o n - c h a n n e l s i n t h e m e m b r a n e o f t h e c e l l t o b e r e c o r d e d a s t h e c h a n n e l o p e n s a n d c l o se s e s . S m a l l ( l x l 0 - v -'-' A ) c u r r e n t p u l s e s a r e r e c o r d e d w i t h t h is is t e c h n i q u e . T h e c u r r e n t s a r e r e c t a n g u l a r i n s h a p e ; C is is t h e c l o s e d s ta ta t e a n d O i s t h e o p e n s ta t a t e. e . ( a ) H i s t o g r a m o f o p e n - t i m e s a n d r e c o r d s o f l e v a m i s o le le - a c ti t i v a te t e d s i n g l e -c - c h a n n e l c u r r e n t s . C e l l - a t ta ta c h e d p a t c h e s . O p e n i n g s d o w n w a r d . P a t c h p o t e n t i a l - 7 5 m V ; 1 0 laM l e v a m i s o l e i n th t h e p a t c h p i p e t t e . M e a n o p e n t i m e : 1 . 34 34 m s . ( b ) A f l ic ic k e r i n g b u r s t d e m o n s t r a t i n g c h a n n e l b l o c k p r o d u c e d b y 3 0 l a st st l e v a m i s o le l e a t - 7 5 m V , c e l l -a - a t t ac ac h e d p a t c h . T h e c o m b e f f e c t o f th t h e c h a n n e l c u r r e n t i s c h a r a c te t e r i st s t i c o f a d r u g m o v i n g i n to to a n d b l o c k i n g t h e i o n - c h a n n e l . ( c ) H i s t o g r a m o f o p e n - t i m e s a n d r e c o r d s o f p y r a n te t e l - a ct c t i v a te t e d s i n g l e -c - c h a n n e l c u r r e n t s . C e l l - a t ta ta c h e d p a t c h ; o p e n i n g s d o w n w a r d ; p a t c h p o t e n t i a l - 7 5 m V ; 0. 0 . 1 I.I.tM m i c r o m o l a r p y r a n t e l i n t h e p a t c h - p i p e t t e . M e a n o p e n - t i m e : 1 .0 .0 9 m s . T h e p y r a n t e l c h a n n e l o p e n t i m e s a r e o n a v e r a g e s l ig i g h t ly ly s h o r t e r t h a n t h o s e o f l e v a m i s o l e .

 

MODES OF ACTION OF ANTHELM INTIC DRUGS Dichlo,wos

mutants with modified nicotinic acetylcholine receptors on muscle (Lewis el al. 1980; Lewis e t al. 1992). (2) Accomnaodation and recovery of parasites after long periods of exposure to the anthelmintics (Lewis et al. 1980; Lewis et al. 1992), and which may be explained by nicotinic receptor desensitization. These resistant or recovered nematodes no longer respond to the nicotinic anthehnintics, but interestingly, may still respond to acetylcholine (Coles et al. 1975). One explanation for these resuhs is that in addition to tile nicotinic receptor on nematode muscle, there are other non-nicotinic cholinergic receptors present on muscle not stimulated by the nicotinic anthelmintics. Such recep tors may facilit facilitate ate contract ion by being coupled via G-proteins to vohage-activated channels.

G e n e t i c s o f r e s i sl s l a n c e to to n i c o t i n i c a n l h e l m i n t i c s

Tile genetics of resistance to the anthelmintic levamisole has been studied in the laboratory using the small fi ee-living ee-living soil nem ato de, C a e n o r habdili.~ eh gans. Several hundred levamisole-resistant alleles have been identified that were isolated ill several screens (Lewis el al. 1980; Lewis e/ a l. 1992). The genes responsible tbr this resistance -1 u n c - 2 9 and u n c - 3 8 that encode tile inclucled: h v -1 proteins subunits that make up the nicotinic ion channels of the nematode. In addition, other genes including: u n c - 50 5 0 u n c - 6 3 and u n c - 7 4 that are believed to be involved in receptor biosynthesis have been identified. Only two strains of lev-1 (×21 and x61) were dom in ant when crossed over with with wildwild-typ types es (nonresistant) (Fleming el al. 1994). The lev-1 (x21) strain only inw~lves mutation at a single aminoacid, replacing glutanaic acid in the ion pore of the receptor ion channel (ill alpha-7 at position 237) 23 7) with a positively-charged lysine. lysine. This c han ge is believed to be sufficient to change the ion channel from cationic to anionic, i.e., to convert tile receptor from an excitatory channel to all inhibitory one. The ~,-1 (x61) swain contains tile amino-acid leucine ill the pore of tile ion-channel i n alpha-7 at position 247): this point mutation is expected to produce increased desensitization and red uced affinity for levamisole levamisole,, render ing l e v a n f i s o l e less potent as an agonist. The genetics of levamisole resistance in parasitic nematodes remains to be studied.

17

o CH30\ l /p

o

H I C] c~ c /

CH30

C1

Haloxon

0 C1CH2CH2 0 /

CH3 F ig ig . 4 .

: h e r o ic ic a l s t r u c t u r e o f d i c h l o r v o s a n d h a l o x o n .

ORGANOPH OSPORUS

C H O L I N E S T E R A SE

INHIBITORS

Dichlmvos

haloxon

Compounds like dichlorvos and haloxon are selective organophosphorus anti-cholinesterases (Fig. 4), and have an anthehnintic action, as well as all insecticidal, action. Dichlorvos and haloxon can control insect parasites, as well as hehninth parasi par asite tes. s. The mode of action action of these compou nds is to block tile action of the parasite enzyme, acetylcholinesterase, leading to the excessive build up of tile neurotransmitter, acetylcholine. This mode of action also predisposes towards toxicity in the host animal where acetylcholinesterase enzymes are also present. Because more selective combined anthehnintic+insecticidal agents (avermectins and milbemycin) are available, the organophosphorus compounds are now used less frequently. The existence of cholinesterase, the enzyme that breaks down acetylcholine, was was first first described in A s c m i s by Bueding (1952). The distribution of cholinesterase was described by Lee (1962) who used histochemical techniques. In the head region of A s c m i s most of the enzyme activity is associated with the contractile spindle region of the muscle and is in the extracellular matrix. L e e (1962) (196 2) also desc ribed chol inest eras e activity activity on the muscle arms near their endings on the n e r v e cords but not on the bag region of the muscle. In C . e le g a n s three classes of acetylcholinesterase are recognized: class A, class B, and class C,

 

,

GA BA

/ ’ \ COOH

,‘A, ‘\ NH;?

H

Piperazine

J

Although acetylcholinesterase is responsible for the break breakdown down of acehllcholine and involve cl iinn motor action in nematodes, it is also secretecl into the external envir environment onment in large quantiti quantities es bv ‘4. .s717077 and other para sitic nem atodes. The fun&on of llle secretecl aceh~lcho linesterase ma), be to reduce the eff effects ects of host ace tylcho line in the intestine, intesti ne, perhaps clecreasing niucosal glanclulai secretion by the host. The original hypothesis of a biochem ical ‘hold-f ‘hold-fast’ ast’ eff effect ect (recluced acetylcholine in the host int intestine estine blocking peristalsis of the gut) has now been rqjecte cl. The identification of the funct function ion of secreted ch olinesterase hy parasitic nematodes, ancl the abilitv to antagonize this enz\me, mav lead to the increased use of‘ anticho linestera ses in the futur futuree to facilitate renio\x l of gut nematodes.

2 pA

100m 100 ms

GA BA A GONIS T

to be produc ts of three separate genes: o wl uw2 cind areare-33 (Opperman & Chan Chang, g, 1992). 1992 ). The three cla sse s of ace tylcholine steras e are sepal-able by their solu bility in Triton, their temperaturee temperatur stability and sens itivity to cholinesterase antago nists. In C. elegcr??.r, elegcr??.r,he he major form form is class B which is distributed distributed in the head and body; classe s A and C have a distribution distribution biased towards the head. Extra ction of the diff different erent clas ses for biochem ical characterization has produced ev idence that the enzyme may exist as a monomer, dim er and tetramer. Defects in the ace-1, m-e-2 mc l ace -j genes sugg est that the functions of the dif diffferent classe s are supplementary but tthat hat if ther theree are defects in all of the genes, then elevated leve ls of acetylcholine occur in C. eleguns and there is

Piperazine has a heteroq~lic ring structure (Fig. .5), ancl unlike y-amino-butyric acid (GABA), lacks a carboxv l group. Howe\*er. Howe\*er. these t~vo con~pou ncls act on th’e th’e same receptor that is a ligancl-galecl Clchannel found on the synaptic ancl extrasynaptic mem brane of nem atocle m uscle (Martin, 198 1980; 0; h4artin. 1982 1982). ). Bath app lication of GA BA or piperazine increa ses the opening of the mus cle mem brme p e r o x y e i c o s a t e t r a e n o i c a c i d s ( 55H P E ' I :E :E ) a n d 5 - 1 a v d r o x v e i c o s a t e t , a e n o i c a c id id s ( 5 - H E T E ) t o t h e l e t , k o t r i e n e s I .T .T A a a n d I +T +T A ~ t o L T C ; i n m a s t c e l ls ls a n d e o s i n o p h i l s . D i e t l~ l~ v l c a r b a m a z i n e i s a l s o s h o w n i n h i b i t i n g t h e c y c h > - o x y g e n a s e e n z y m e t h a t c o n v e r t s a , a c h i d o n i c a c i d t o t h e pro st agl m ]di n s P( P(~G ~G.._,an d P(; P(;H H ._,. ._,. T he sub seq ue nt pro du ct i o n of P(; P(;D_,. D_,. PG E=,, E=,, PG I=, & TY~ TY~-k,_,i s al so i nhi b i t ed i n t he bl o od vessels and ,nicrol]lari;~.

w i th t h d i e t h y l c a r b a m a z i n e , r e d u c e s t h e e ff f f e ct ct o f dietlaylcarhamazine ( S t i n g l e l a l. 1988). Thus, d i e t h y l c a r b m n a z i n e s e e m s to t o i n h i b it it p r o d u c t i o n o f PG P G I= I= , a n d P GE G E =, =, h y m i c r o f i l a r i a a n d e n d o t h e l i a l c e ll l l s. s . T h e n o r m a l l ev e v e l o f p r o d u c t i o n o f PG P G 1 ._ , a n d P GE G E ,_ ,_ , t h a t p r o d u c e s a t o n i c d i l a t i o n o f b l o o d v e s s el e l s a n d i n h i b i t s a g g r e g a t i o n o f n e u t r o p l a i ls ls a n d eosinoph ils is r e d u c e d by administration of

f i la l a r i ae a e a n d c y t o t o x i c a c t iv iv i g , b y t h e h o s t p l a t e l e t s and granulocytes. It appears that diethylcarbam azi n e a c ti t i v at a t es es a n in n a t e i m m u n e r e s p o n s e r a t h e r t h a n a n a d a p t i v e i m m u n e r e s p o n s e ( M a i z e ls ls & D e n h a m , 1 9 9 2) 2) . T h i s m o d e o f a c t i o n c a n e x p l a in w h y d i e t h y l c a r b a m a z i n e h a s n o a c t io n in v itr o a g a i n s t m i c r o f i l a r ia i a e a n d i s e f f e c ti t i v e in in n o n immune animals.

diethylcarhamazine. A p la l a u s i b le le e x p l a n a t i o n o f t h e m o d e o f a c t i o n o f d i e t h y l c a r b a m a z i n e i s t h a t th t h is i s c o m p o u n d a l t er er s t h e m e t a b o l i s m o f a r a c h i d o n i c a c i d s in h o s t e n d o t h e l i a l c e ll l l a n d a l s o in i n m i c r o f i l a r i a e t h a t a r e s u ssc e p t i b le

to

th e th

action

of

diethylcarbamazine.

T h e r e is t h e n a v a s o c o n s t r i c t i o n , a m p l i f i e d e n d o t h el e l ia ia l a d h e s i o n a n d i m m o b i l i z a t i o n o f t h e m i c r o -

 

CKNOWLEDGEMENTS

I a m p l e a s e d t o a c k n o w l e d g e t h e f in in a n c i a l s u p p o r t of the We llcome Trust who have supported my work on the electrophysiology of the piperazine,

32

THE VETERINARY JOURN AL, 154, 1

n i c o t in in i c a n t h e l m i n t i c s a n d t h e G I u C i r e c e p t o r s o f A sc a ,i s.

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Ascmqs B~itish sh Jou rnal of Pharmacol Pharmacology ogy 3 8 3 3 2 -s4o4m. a t i c m u s c l e . B~iti Aa..VI Aa VINEm NEmE, E, M ., Ft.oc'tl, R . & GAI.'rlER, GAI.'rlER,P. (1 99 5) . Pl as m a p r o t e i n b i n d i n g o f n i t r o x y n i l i n se s e v e r a l s p e c i e s Journa l o f Veterinary Pha~vnacology an d Therapeutics. 14, 170-3. ANDREWS, P., TIIOSL~ TIIOSL~';';,, H ., Po m .~ , R . & SEUBERT, J . ( 1 9 8 3 ) . P r a z i q u a n t e l . Med ical Research Reviews. 3,

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MODES OF ACTION OF ANTHELMINTIC DRUGS

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