RELATIONSHIP BETWEEN CLONIDINE KINETICS AND ITS BLOOD

PRESSURE EFFECTS

Marianne Frisk-Holmberg

Lennart Paalzow

Section Clin. Pharm., Medical School, Dept. Pharmacol. Pharm.,

BMC, and Hypertension Clinic, University Hospital, Uppsala

University, 5-751 23 Uppsala, Sweden.

Clonidine in daily doses from 0.075-1.2 mg is used in

Scandinavia for the treatment of essential hypertension.

Higher doses are used elsewhere and during chronic admini-

stration with approximately 5 . 4 mg daily giving peak plasma

concentrations ~ 2 0 ng/ml the therapeutic response was abolished . Davies et a1.l studying healthy volunteers have also reported

that the blood pressure lowering effect is reduced when higher

plasma concentrations of clonidine are present. After bolus

doses of 0.15-0.3 mg a hypertensive response has been ob-

served in man . Higher doses give a more pronounced blood pressure increase. These studies indicate a concentration

dependence of clonidine’s blood pressure effects. The aim

of the present investigation was to study relationship between

clonidine kinetics and the therapeutic response in essential

hypertensives after bolus injections. To study the concentra-

tion dependence of the blood pressure effects during steady

state conditions the spontaneous hypertensive rat (SHR) was

investigated.

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5

PATIENTS

13 previously untreated healthy patients of both sexes

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( 3 women) p a r t i c i p a t e d . They were informed of t h e a i m of

t h e s tudy and gave t h e i r w r i t t e n consent . A f t e r i n v e s t i g a -

t i o n a t t h e Hypertension C l i n i c they w e r e c l a s s i f i e d a s

having an e s s e n t i a l hyper tens ion corresponding t o WHO s t a g e

1-11. The blood p r e s s u r e w a s expressed as mean a r t e r i a l

pressure .6 I t was based on 3 s e p a r a t e ambulant p r e s s u r e re-

cord ings , t h e group mean v a l u e was 11725 mm Hg. The mean age

was 4625 y e a r s . 2 0 % of t h e p a t i e n t s belonged to t h e l o w r e n i n

group accord ing t o t h e i r f a s t i n g plasma r e n i n a c t i v i t y / 2 4 h r

u r i n e sodium e x c r e t i o n index. The i n v e s t i g a t i o n was performed

wi th t h e p a t i e n t s supine . An i n t r a v e n o u s cannula w a s i n s e r t e d

i n both forearms, one f o r i n j e c t i o n and one f o r sampling.

Clonidine w a s given as bolus i n j e c t i o n s i n doses from 75 t o

275 pg. 9 p a t i e n t s rece ived 2 doses a t s e p a r a t e o c c a s i o n s .

Heart frequency and blood p r e s s u r e was measured non-invasively

by t h e same person w i t h a mercury sphygmomanometer e v e r y

15 min t h e h r b e f o r e t h e i n j e c t i o n and accord ing to a pre-

determined p r o t o c o l d u r i n g 2 4 h r s a f t e r t h e i n j e c t i o n as de-

s c r i b e d . Venous samples f o r c l o n i d i n e d e t e r m i n a t i o n s were

drawn i n connect ion wi th t h e p r e s s u r e r e c o r d i n g s . Concentra-

t i o n t i m e d a t a f o r each s u b j e c t were t h e n t r e a t e d w i t h a

d i g i t a l computer program ( N O N L I N ) t o f i n d t h e b e s t f i t of a

polyexponent ia l equat ion . All v a l u e were weighted and g iven

a s mean 2 S . D . a s d e s c r i b e d . 3

SHR experiments: Blood p r e s s u r e was r e g i s t e r e d from an ca the-

ter i n t h e a . c a r o t i s on awake SHR. Through an i n d w e l l i n g

c a t h e t e r i n v. j u g u l a r i s c l o n i d i n e was i n f u s e d a t d i f f e r e n t

r a t e s t o achieve s t e a d y s ta te plasma c o n c e n t r a t i o n between

0.5-10 ng/ml, a s d e ~ c r i b e d . ~ 5-6 r a t s w e r e s t u d i e d a t each

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s t e a d y s ta te level . Venous s a m p l i n g f o r c l o n i d i n e a n a l y s i s

were drawn. Va lues a r e mean ? S.D.

C l o n i d i n e was d e t e r m i n e d i n p lasma w i t h a g a s l i q u i d 2 c h r o m a t o g r a f i c method u s i n g a n e l e c t r o n - c a p t u r e d e t e c t o r .

RESULTS

C l o n i d i n e k i n e t i c s . A f t e r b o l u s i . v . d o s e s (0 .075-0.275 mg)

t h e p lasma c o n c e n t r a t i o n t i m e c u r v e s d i s p l a y e d a b i e x p o n e n t i a l

decay , d u r i n g 0-1440 min. The k i n e t i c s of c l o n i d i n e w a s d e s c r i b e d

by an open 2-compartment model . The h a l f - l i f e f o r t h e a -phase

v a r i e d between 2.4-15.1 min. and €or t h e f3-phase be tween

7 . 4 - 1 1 . 4 h r s . N o s i g n i f i c a n t d i f f e r e n c e be tween t h e h a l f -

l i v e s a f t e r t h e d i f f e r e n t d o s e s w a s found b u t t h e d e c a y of

b o t h t h e a -phase and t h e @-phase w a s d e c r e a s e d a f t e r t h e

h i g h e s t d o s e (0.275 mg). The a p p a r e n t volume of t h e d i s t r i b u -

t i o n (VDf3) w a s 3 .29 l / k g and u n a f f e c t e d by dose. A g r a d u a l

i n c r e a s e i n t h e area unde r t h e p lasma c o n c e n t r a t i o n c u r v e

w a s o b s e r v e d between t h e 0.075-0.2 mg (256.22544 min/ml) and

t h e h i g h e s t dose 0.275 mg (386 min/ml) . The mean p lasma

c l e a r a n c e w a s 4 ml/min/kg (0.075-0.2 mg) and w a s lower a f t e r

t h e 0.275 m g dose (2 .98 ml /min /kg) .

R e l a t i o n s h i p c l o n i d i n e k i n e t i c s and t h e r a p e u t i c r e s p o n s e

C l o n i d i n e gave a dose-dependent blood p r e s s u r e r e d u c t i o n .

The blood p r e s s u r e d e c r e a s e w a s s i g n i f i c a n t l y correlated t o

t h e l o g a r i t h m o f t h e d o s e ( r=0 .975 , p<O.OOl) f rom t h e 0.075 rng

dose to 0.275 mg. The dose - re sponse c u r v e w a s s t e e p . The

mean a r t e r i a l b l o o d p r e s s u r e r e d u c t i o n w a s 3825.29 mm H g a f t e r

t h e h i g h e s t dose. The h e a r t r a te w a s a l s o r e d u c e d b u t t h e

r e d u c t i o n w a s n o t dose related. N o r e l a t i o n s h i p w a s found

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between t h e p a t i e n t s "plasma r e n i n s t a t u s " and t h e b lood

p r e s s u r e e f f e c t . The b lood p r e s s u r e r e d u c t i o n was a l so s i g -

n i f i c a n t l y correlated t o t h e l o g a r i t h m of t h e plasma con-

c e n t r a t i o n o f c l o n i d i n e ( r=0 .86 , p<O.Ol) . C o n c e n t r a t i o n s

above 0.2 ng/ml gave a s i g n i f i c a n t b lood p r e s s u r e decrease.

A f t e r doses of 0.2-0.275 mg t h e b lood p r e s s u r e r e d u c t i o n was

s t i l l p r e s e n t a t t h e 2 4 h r s o b s e r v a t i o n . A p o s i t i v e corre-

l a t i o n w a s a lso found between c l o n i d i n e plasma c o n c e n t r a -

t i o n s and t h e b lood p r e s s u r e r e d u c t i o n a l l o b s e r v a t i o n p o i n t s

s t a r t i n g a f t e r t h e d i s t r i b u t i o n phase ( F i g . l), when an appa-

r e n t p s e u d o e q u i l i b r i u m i s a c h i e v e d ( r = 0 . 8 9 , p c 0 . 0 2 ) .

R e l a t i o n s h i p c l o n i d i n e s t e a d y s ta te c o n c e n t r a t i o n s (CFasL

and b lood p r e s s u r e e f f e c t s (SHR)

C c o n c e n t r a t i o n s o f 0 , 5 ng/ml gave a s i g n i f i c a n t re- PSS

d u c t i o n of mean a r t e r i a l blood p r e s s u r e , 5+2 nun Hg (p<0 .05 ;

n=5) . The b lood p r e s s u r e r e d u c t i o n w a s l i n e a r y related t o

t h e C o f c l o n i d i n e up t o l e v e l s of 2 .0 ng/ml. Above t h a t

l eve l t h e b lood p r e s s u r e r e d u c i n g e f f e c t o f c l o n i d i n e w a s

a t t e n u a t e d and a t l e v e l s of 8 .0 and 10 ng/ml a b l o o d p r e s s u r e

i n c r e a s e w a s s e e n . These a n i m a l data i n d i c a t e t h a t c l o n i -

d i n e h a s a narrow plasma c o n c e n t r a t i o n r a n g e f o r i t s b lood

p r e s s u r e r e d u c i n g e f fec t .

PSS

DISCUSSION

The p r e s e n t d a t a show t h a t a f t e r i . v . b o l u s o f c l o n i d i n e

t h e r e i s a s i g n i f i c a n t c o r r e l a t i o n between t h e t h e r a p e u t i c

e f f e c t and t h e plasma c o n c e n t r a t i o n o f c l o n i d i n e a t a l l ob-

s e r v a t i o n p o i n t s when a n a p p a r e n t p s e u d o e q u i l i b r i u m o f t h e

d r u g i s ach ieved . The pha rmacok ine t i c s o f c l o n i d i n e show t h a t

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t h e volume of d i s t r i b u t i o n i s h i g h and t h e mean plasma

c l e a r a n c e i s 4 ml/min/kg. The h a l f - l i f e of t h e t e r m i n a l

plasma c o n c e n t r a t i o n curve between 7-11 h r s , and a f t e r s i n g l e

d o s e s of 0 .10 mg o r more blood p r e s s u r e lowering plasma con-

c e n t r a t i o n s of c l o n i d i n e a r e s t i l l p r e s e n t 12 h r s a f t e r t h e

a d m i n i s t r a t i o n . This f a c t would a l l o w a 2 dose regimen.

During s t e a d y s t a t e c o n d i t i o n s i n t h e SHR, c l o n i d i n e h a s

a narrow plasma c o n c e n t r a t i o n range f o r i t s blood p r e s s u r e

lowering e f f e c t i n d i c a t i n g a " t h e r a p e u t i c window". T h i s ob-

s e r v a t i o n could be one e x p l a n a t i o n € o r t h e t h e r a p e u t i c v a r i a -

b i l i t y and i n e f f i c i e n c y of t h e drug i n t h e c l i n i c a l s i t u a t i o n .

CHANGE IN MAP mm Hg 40

0 100.

30

20 251

I I I 0.40 1.0 3.0

Figure legend

R e l a t i o n s h i p between r e d u c t i o n of mean blood p r e s s u r e ( M A P ) ,

mean v a l u e of i n d i v i d u a l v a l u e s , and mean plasma c l o n i d i n e

c o n c e n t r a t i o n a f t e r i . v . doses of 0.075-0.275 mg ( log s c a l e ) ,

a t a l l p o i n t s of t i m e d u r i n g pseudoequi l ibr ium of t h e d i s -

' * t r i b u t i o n .

REFERENCES

1. Davies, D.S., Wing, L.M., Reid, I.L.", Neill, P.,

Tippett, P., Dollery, C.G., Pharmacokinetics and concentra-

tion effect relationships of intravenous and oral clonidine.

Clin. Pharma. Ther. 1977, 21, 593-601.

2 . Edlund, I.O., Paalzow, L., Quantitative gas liquid chroma-

tograpic determination of clonidine in plasma. Acta pharmacol

toxicol. 1977, 40, 145-152.

3. Frisk-Holmberg, M., Edlund, P.O., Paalzow, L., Relation-

ship between clonidine kinetics and its therapeutic effect.

Br. J. Clin. Pharmacol., 1978 in press.

4. Frisk-Holmberg, M., Gunnarsson, C., Paalzow, L., Concentra-

tion dependence of the blood pressure effects of clonidine.

J. Pharm. Pharmacol. to be published.

5. Kroetz, F., McRaven, D., Kioschoz, I.M., Kirkenwall, W.M.,

The acute effects of catapresan cardiac hemodynamics of

hypertensive mean,in Catapres in hypertension, Ed. M.E.

Conolly, Butterworth, London, pp.39-69.

6. Rashemer, R.F., In. Cardiovascular dynamics, 2nd ed.

W.B. Sunders Col, Ltd, Philadelphia and London, 1968,

p. 343.

7 . Wing, L.M.H., Reid, I.L., Davies, D.S. Dargie, H.J.,

Dollery, C.T., Apparent resistance to the hypotensive

effect of clonidine. Brit. Med. J., 1977, 1, 136-138.

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