withdrawal syndromes following cessation of treatment with antihypertensive drugs

7
Gen Pharma~ Vol 13 pp 79 to 85 1982 0306-3623/82/020079-0750500/0 Printed in Great Brnam All rights reserved Copyright © 1982 Pergamon Press Ltd MINIREVIEW WITHDRAWAL SYNDROMES FOLLOWING CESSATION OF TREATMENT WITH ANTIHYPERTENSIVE DRUGS M PARKER and J ATKINSON Instltut de Pharmacologle de l'Umverslt6, CH-1011 Lausanne, Switzerland (Recewed 13 July 1981) INTRODUCTION As essentml hypertension occurs with a frequency of about 20% in certain communities (Abernethy, 1974, Labarthe, 1976) and as it is now generally accepted that chronic lowering of blood pressure especially m moderate to severe hypertension prolongs life, this means that a large number of people are taking anti- hypertensive drugs for long periods of time As in any long-term treatment, ~t ~s not surprising that situ- ations arise when the drug treatment is interrupted a patient may require surgery or a change of treatment due to side effects, or he may forget or be unable to take his usual dose Abrupt interruption of chronic treatment is not always harmless and it is now rea- hsed that a sudden interruption of chronic therapy w~th certain antlhypertenswe drugs may have very serious consequences Recognition of the problems associated with sud- den interruption of antihypertensive therapy came with the description of a withdrawal syndrome fol- lowing cessation of long term treatment with the cen- tral antihypertenslve agent, clonldlne Thus Hokfelt et al (1968, 1970) reported that symptoms indicative of excessive catecholamme release such as hypertension, tachycardia, headache, anxiety, tremor, sweating, nau- sea and vommng occurred in some patients when their chronic clomdme treatment was abruptly stopped This report was then followed by numerous anecdotes of clomdlne withdrawal phenomena and ItS occurrence in chmcal trials (Conoily et al, 1972, Hansson & Hunyor, 1973, Hunyor et al, 1973, Rosei et al, 1976, Spach et al, 1977, Reid et al, 1977, Yud- kin, 1977) Discontinuation of other centrally acting antlhypertenswe agents may also reduce withdrawal syndromes The clomdme analogue, guanfacme, may reduce withdrawal phenomena though the incidence of this seems to be less than that associated with clomdme (Jaattela, 1976, Seedat, 1978, Klrch & Dis- tier, 1978, Jene, 1980, Szam & Hollo, 1981) With- drawal phenomena have also been described follow- mg cessation of methyldopa (Burden & Alexander, 1976, Scott & McDevitt, 1976, Frewm & Penhall, 1977, Mroczek & Davidov, 1978) and guanabenz (Ram et al, 1979) Drugs which act prtmanly on the peripheral sympathetic nervous system such as the adrenergic neurone blocking agents bethamdme, gua- nadrel and guanethidme (Mroczek & Davidov, 1978, Goldberg et al, 1977) can also lnduee withdrawal phenomena However it ~s interesting to note that the frequently prescribed beta-adrenerglc receptor block- 'mg drugs, such a propranolol, rarely cause rebound of blood pressure and/or heart rate when chronic ther- apy is stopped (Kmcald-Smlth et al, 1976, Rangno et al, 1981) Particular care should be taken when such beta-adrenoreceptor antagonists are used m conJunc- tion with clomdme as they may accentuate the with- drawal effects of ciomdme (Vernon & Sakula, 1979, Weber, 1978) Caution should also be taken when withdrawing patients who have had a history of coronary artery disease from beta-adrenoreceptor an- tagomsts Many reports have appeared in whlch stop- ping treatment with propranoiol (or other beta blockers) has led to sometimes fatal lschemxc events and symptoms suggestive of thyrotoxlcosls (O'Brlen & Macklnon, 1972, Slome, 1973, Mlzgala & Coun- sell, 1974, Mdler et al, 1975, Allen & Genovese, 1975, Pedersen, 1976, Myers & Wlsenberg, 1977, Knsten- sen et al, 1978) Antlhypertenslve drugs whose mechanism of action is independent of central and peripheral sympathetic nervous system (such as direct vasodllators or con- vertmg enzyme mhlbltors) do not appear to induce a w~thdrawal syndrome Abrupt cessation of chronic treatment with angiotensm convertmg enzyme mhibi- tors (during which plasma renm activity may rise to very high levels) could be expected to produce a large, anglotensm II induced, blood pressure overshoot Although this has been reported to occur in sodmm- depleted sheep (Scogglns et al, 1981), rebound hyper- tension followmg abrupt cessation of angiotensm con- vertmg enzyme inhibition would not appear to be a common phenomenon Likewise direct vasodllators which stimulate renln release may be expected to induce rebound hypertension but this has rarely been observed (Cottrell et al, 1980) Th~s mm~revlew will therefore concentrate on with- drawal syndromes following cessation of treatment with centrally acting antl-hypertenswe drugs, es- pecially clomdme THE NATUREOF THE WITHDRAWAL SYNDROME CLINICAL STUDIES The hfe-threatemng symptom of the withdrawal phenomenon is elevated blood pressure and it is tills that has received the most attention Various ques- tions have been posed the answers are as yet unclear F~rstly, is there, in fact, a true "rebound" of blood 79

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Gen Pharma~ Vol 13 pp 79 to 85 1982 0306-3623/82/020079-0750500/0 Printed in Great Brnam All rights reserved Copyright © 1982 Pergamon Press Ltd

MINIREVIEW

W I T H D R A W A L S Y N D R O M E S F O L L O W I N G CESSATION OF T R E A T M E N T WITH A N T I H Y P E R T E N S I V E D R U G S

M PARKER and J ATKINSON Instltut de Pharmacologle de l'Umverslt6, CH-1011 Lausanne, Switzerland

(Recewed 13 July 1981)

I N T R O D U C T I O N

As essentml hypertension occurs with a frequency of about 20% in certain communities (Abernethy, 1974, Labarthe, 1976) and as it is now generally accepted that chronic lowering of blood pressure especially m moderate to severe hypertension prolongs life, this means that a large number of people are taking anti- hypertensive drugs for long periods of time As in any long-term treatment, ~t ~s not surprising that situ- ations arise when the drug treatment is interrupted a patient may require surgery or a change of treatment due to side effects, or he may forget or be unable to take his usual dose Abrupt interruption of chronic treatment is not always harmless and it is now rea- hsed that a sudden interruption of chronic therapy w~th certain antlhypertenswe drugs may have very serious consequences

Recognition of the problems associated with sud- den interruption of antihypertensive therapy came with the description of a withdrawal syndrome fol- lowing cessation of long term treatment with the cen- tral antihypertenslve agent, clonldlne Thus Hokfelt et al (1968, 1970) reported that symptoms indicative of excessive catecholamme release such as hypertension, tachycardia, headache, anxiety, tremor, sweating, nau- sea and vommng occurred in some patients when their chronic clomdme treatment was abruptly stopped This report was then followed by numerous anecdotes of clomdlne withdrawal phenomena and ItS occurrence in chmcal trials (Conoily et al, 1972, Hansson & Hunyor, 1973, Hunyor et al, 1973, Rosei et al, 1976, Spach et al, 1977, Reid et al, 1977, Yud- kin, 1977) Discontinuation of other centrally acting antlhypertenswe agents may also reduce withdrawal syndromes The clomdme analogue, guanfacme, may reduce withdrawal phenomena though the incidence of this seems to be less than that associated with clomdme (Jaattela, 1976, Seedat, 1978, Klrch & Dis- tier, 1978, Jene, 1980, Szam & Hollo, 1981) With- drawal phenomena have also been described follow- mg cessation of methyldopa (Burden & Alexander, 1976, Scott & McDevitt, 1976, Frewm & Penhall, 1977, Mroczek & Davidov, 1978) and guanabenz (Ram et al, 1979) Drugs which act prtmanly on the peripheral sympathetic nervous system such as the adrenergic neurone blocking agents bethamdme, gua- nadrel and guanethidme (Mroczek & Davidov, 1978, Goldberg et al, 1977) can also lnduee withdrawal phenomena However it ~s interesting to note that the

frequently prescribed beta-adrenerglc receptor block- ' m g drugs, such a propranolol, rarely cause rebound of

blood pressure and/or heart rate when chronic ther- apy is stopped (Kmcald-Smlth et al, 1976, Rangno et al, 1981) Particular care should be taken when such beta-adrenoreceptor antagonists are used m conJunc- tion with clomdme as they may accentuate the with- drawal effects of ciomdme (Vernon & Sakula, 1979, Weber, 1978) Caution should also be taken when withdrawing patients who have had a history of coronary artery disease from beta-adrenoreceptor an- tagomsts Many reports have appeared in whlch stop- ping treatment with propranoiol (or other beta blockers) has led to sometimes fatal lschemxc events and symptoms suggestive of thyrotoxlcosls (O'Brlen & Macklnon, 1972, Slome, 1973, Mlzgala & Coun- sell, 1974, Mdler et al, 1975, Allen & Genovese, 1975, Pedersen, 1976, Myers & Wlsenberg, 1977, Knsten- sen et al, 1978)

Antlhypertenslve drugs whose mechanism of action is independent of central and peripheral sympathetic nervous system (such as direct vasodllators or con- vertmg enzyme mhlbltors) do not appear to induce a w~thdrawal syndrome Abrupt cessation of chronic treatment with angiotensm convertmg enzyme mhibi- tors (during which plasma renm activity may rise to very high levels) could be expected to produce a large, anglotensm II induced, blood pressure overshoot Although this has been reported to occur in sodmm- depleted sheep (Scogglns et al, 1981), rebound hyper- tension followmg abrupt cessation of angiotensm con- vertmg enzyme inhibition would not appear to be a common phenomenon Likewise direct vasodllators which stimulate renln release may be expected to induce rebound hypertension but this has rarely been observed (Cottrell et al, 1980)

Th~s mm~revlew will therefore concentrate on with- drawal syndromes following cessation of treatment with centrally acting antl-hypertenswe drugs, es- pecially clomdme

THE NATURE OF THE WITHDRAWAL SYNDROME CLINICAL STUDIES

The hfe-threatemng symptom of the withdrawal phenomenon is elevated blood pressure and it is tills that has received the most attention Various ques- tions have been posed the answers are as yet unclear

F~rstly, is there, in fact, a true "rebound" of blood

79

80 M PARKER and J ATKINSON

pressure to levels higher than those observed before treatment, or simply a return to values determined by the natural progression of the disease that was masked during treatment9 On stopping chronic clom- dine treatment an abrupt rebound of the blood press- ure to values higher than those recorded before treat- ment has been reported by several authors (Hansson et al, 1973, Rosel et al, 1976, Yudkin, 1977) In a study reported by Jerle (1980), of 407 patients with- drawn from guanfacme, 9 experienced a rebound in- crease in blood pressure and 6 of these 9 had blood pressures higher than pretreatment values Reid et al (1977), however, reported that during withdrawal from clomdme the blood pressures of his patients did not exceed their pretreatment blood pressures An unequivocal reply to the question of whether or not rebound overshoot of blood pressure and/or heart rate occurs, cannot be formulated, as (a) pretreatment blood pressures and heart rates are rarely measured in clinical trials and (b) data from corresponding con- trols (receiving placebo) with a similar pretreatment medical history to the patients receiving antihyperten- sive therapy is also rarely available

A second question of great clinical importance is. Is the occurrence of the withdrawal phenomena depen- dent on the dose of the drug, the duration of therapy and/or the severity of the pretreatment hypertension9 Again it is not clear from clinical data to what extent withdrawal phenomena are dependent on these factors

Goldberg et al (1976) suggested that the severity of the rebound m blood pressure was related to the dose of clomdme Likewise, Ram et al (1979) showed that the intensity of the withdrawal syndrome after cessa- tion of treatment with guanabenz was also related to dose Mroczek & Davldov (1978), however, suggested that the severity of the withdrawal syndrome was related to the duration of therapy (with clonldine) rather than to dose or to pretreatment blood pressure It appeared from their data that patients with a his- tory of increased blood pressure lability were more likely to show withdrawal symptoms Whltsett et al (1976) suggested that rebound hypertension following clomdme withdrawal was less likely to occur in patients with initial mild to moderate hypertension since they found no rebound m blood pressure in such patients after cessation of 4 weeks treatment with clonidme

It has also been suggested that gradual (rather than abrupt) withdrawal of antlhypertensive therapy is less likely to produce withdrawal symptoms, however this is not infallible and rebound phenomena may still occur (Wdklnson et al, 1975, Goldberg et al, 1976, Stelzer et al, 1976, Strauss et al, 1977)

Finally it should not be forgotten that clonldine (and, presumably, other hpophdic alpha adrenorecep- tor agonists which lower blood pressure by stimu- lation of cerebral alpha adrenoreceptors) has a rela- tively narrow "therapeutic window" as its central blood pressure lowering effect is counteracted by its peripheral pressor effect on postsynaptic vascular alpha adrenoreceptors which causes hypertension (Reid et al, 1980) It may be that only treatment sche- dules of dose and duration such that plasma levels of clonidlne fall in the middle of this therapeutic window (and this for long enough periods), are capable of

inducing withdrawal because only these schedules induce (potentially) maximal falls m blood pressure

A third and final theoretical question is What are the biochemical mechanisms involved m antihyper- tensive drug withdrawal9

There have been few biochemical studies made dur- ing the phase of antihypertenswe drug withdrawal an clinical trials Sparse information is available on plasma and urinary catecholamlne levels after clom- dine withdrawal Hansson et al (1973) reported that total arterial catecholamlnes were not significantly m- creased m 5 patients who experienced rebound of blood pressure and other withdrawal symptoms but that urinary catecholamlne levels were mcreased slg- mficantly Reid et al (1977) found a significant m- crease m both urinary and plasma catecholamlnes during withdrawal of clomdme In two cases reported by Conolly et al (1972) there were long lasting m- creases In plasma and urinary catecholamines assoo- ated with withdrawal which continued for five days after the cessation ofclonldlne No data was available on the catecholamlne levels prior to treatment Reid et al (1980) found an increase in plasma noradrena- line levels m patients after guanfacme (and clomdme) withdrawal (even in the absence of rebound hyper- tension), urinary noradrenahne was not increased

On the basis of the coincidence m time of the m- creased urinary noradrenahne excretion with the m- crease m blood pressure and heart rate, Geyskes and coworkers (1979) drew the conclusion that an increase in the activity of the sympathetic nervous system was mainly responsible for the clonldme withdrawal blood pressure increase On the other hand they found that plasma renm activity fell during early withdrawal and rose later (48 hr after withdrawal) They concluded that the renln-angiotensin system does not play a role m the rebound hypertension This is confirmed by the recent report of Hauger-Klevene (1981) In summary it can be stated that the rebound increases m blood pressure observed following cessation of chronic treatment with centrally acting antlhypertenslve agents are probably provoked by an increase m peri- pheral sympathetic nervous system activity There is no clinical data on possible changes m central ner- vous system activity

As clinical trials are obviously ethically hmlted m their capacity to provide answers to the questions posed above, many workers have turned to ammai models

THE NATURE OF THE WITHDRAWAL SYNDROME

ANIMAL MODELS

These have certain advantages for example pre- treatment blood pressures and heart rates are easily obtainable, placebo, control groups can be run In parallel with treated groups, etc Thus our first ques- tion has been answered the rebound increases m blood pressure and/or heart rate to levels higher than those observed before treatment do occur in animals following cessation of chronic treatment with cen- trally acting antlhypertenslve agents A complete answer to the second question as to whether with- drawal phenomena are dependent on dose and/or duration of therapy and on pretreatment blood press- ure (and heart rate) values, cannot be given, however

Withdrawal symptoms from antlhypertenslve drugs 81

Finch et al (1978) and Finch & Hicks (1980) con- sidered that rebound in blood pressure following clonldine withdrawal was dose-dependent (in con- scious hypertensive cats), whereas (in anesthetized normotensive rats), Oates et al (1978) found the rebound elevations of blood pressure and heart rate following clonidme or guanfaclne were not dose- dependent Apart from the difference in the animal model used, the discrepancy between these two groups may be explained on the basis of the narrow therapeutic window for clonidine mentioned above Thus Distefano et al (1980) stated that treatment with all hypotensive doses of clonldane, which are situated in this relatively narrow hypotensive range, can potentially produce withdrawal when abruptly stopped This idea is also evident from the work of Prop (1978) who observed a rebound hypertension following cessahon of low dose clonldlne treatment (005 mg kg-I 24hr i in drinking water) but none following higher dose clonidane treatment (which, in fact, was hypertensive in itself)

Studies on the influence of the duration of treat- ment on the occurrence of rebound such as that of Oates et al (1978) have demonstrated that the same degree of rebound occurs in anesthetized rats whether they have been treated with clonldlne or guanfaclne for short or long periods 3 days, 3 weeks, or given a single injection In relation to the occurrence of rebound after a single dose of clonidlne, in a recent study (Parker et al, 1980) we were unable to demon- strate a rebound of blood pressure or heart rate after a single dose of clonldlne in conscious rats using a similar protocol to that of Oates et al (1978) Cavero et al (1977) observed a rebound hypertension and tachycardia in conscious renal hypertensive dogs after 4 and 10 days of treatment with clonidlne However, Finch & Hicks (1980) found no withdrawal rebound of blood pressure or heart rate in renal hypertensive cats following 10 days treatment with a long acting preparation of clonldlne The use of a long acting preparation perhaps avoids the situation observed by Salzmann (1979) and Prop (1978) of major fluctu- ations in blood pressure and heart rate occurring dur- ing the treatment period Administration of clonidlne by osmotic minipumps to rats over a period of 7 or 9 days, a system which gives a constant delivery of drug during the treatment period resulted in a rebound elevation of blood pressure after withdrawal (Atkin- son et al, unpublished observations) When clonidlne was given In the drinking water for 1-21 days, no withdrawal symptoms were seen after 1-3 days of treatment whereas maximal withdrawal symptoms were seen after 7-10 days (Distefano et al, 1980)

It would appear that clonidlne (and probably other centrally acting antlhypertenslve agents) should be given for at least one week in order to reliably pro- duce rebound hypertension and/or tachycardla upon cessation

The question of whether the initial blood pressure and heart rate values determine whether or not rebound will occur has not been clarified Some authors have reported a rebound of blood pressure and/or heart rate after clonldine withdrawal in nor- motenslve animals (Dix & Johnson, 1977, Oates et al, 1978, Prop, 1978, Atkinson et al 1979, Salzmann, 1979) However, Finch et al (1978) observed a

rebound of heart rate and in some cases blood press- ure m renal hypertensive cats but not in normotenslve cats and Cavero and coworkers (1977) observed a rebound of blood pressure and heart rate in 4 out of 6 renal hypertensive cats and in 3 renal hypertensive dogs after clonidine withdrawal but no rebound (only a return to pretreatment levels of blood pressure and heart rate in normotensive and spontaneously hyper- tensive rats In a comparative study between normo- tensive, spontaneously hypertensive and renal hyper- tensive rats, Atkinson and coworkers (1979) found that 38, 100 and 32~o respectively exhibited rebound hypertension after withdrawal of clonldlne given in the drinking water However, Dmtefano and co- workers (1980) using a very similar protocol found rebound tachycardla but no elevation in blood press- ure upon cessation of chronic clonidine treatment in normotenslve rats, and Yomaida et al (1979) failed to produce blood pressure overshoot in spontaneously hypertensive rats upon cessation of a treatment sche- dule again similar to that used by Atkinson et al (1979)

A true answer to the question as to whether initial blood pressure and/or heart rate values (and other factors such as species) affect the withdrawal increases in cardiovascular activity must await standardisatton of narameters such as dose, duration of treatment, etc

Our third and lanai question concerns the bio- chemical mechanisms underlying the withdrawal phenomena From the clinical data presented above it would appear that withdrawal phenomena are caused primarily by a sudden increase in peripheral sympath- etic nervous system activity This is suggestive of a "breakdown" of cerebral control of peripheral sym- pathetic activity, We would suggest that this "break- down" arises in the following way Alpha sympathlco- mimetic substances which are anti-hypertensive act by preferential stimulation of cerebral alpha adrenore- ceptors Such stimulation activates a central modulat- ing system which &mlnlshes peripheral sympathetic activity (and, possibly, Increases peripheral parasym- pathetic, vagal activity) and so lowers blood pressure, simultaneously the central endogenous neurotrans- mitter system which normally stimulates these modu- latory alpha adrenoreceptors is "turned off' When treatment with the exogenous agent is abruptly ter- minated, the animal (or human being) is incapable of modulating peripheral sympathetic activity (until the endogenous system is reestablished) and rebound occurs

Let us now examine the evidence for this hypoth- esis Numerous experiments have established the fact that centrally acting antihypertensive agents lower blood pressure by stimulation of post-synaptic alpha adrenoreceptors in the baroreceptor-modulatmg centre of the nucleus tractus sohtaru, activating in- hibitory buibar lnterneurons (for review see Hoefke, 1980) Future research may further refine this basic idea for example, these agents may be acting on receptors for adrenaline rather than those for nor- adrenahne (Fuxe et al, 1980) or on receptors which are similar to but not the same as alpha adrenorecep- tors (Korner et al, 1980), other neurotransmitter sub- stances such as endogenous peptides may be involved, etc but will probably not change its fundamental con- cept l e centrally acting antihypertensive agents

82 M PARKER and J ATKINSON

lower blood pressure by stimulation of post-synaptlc alpha adrenoreceptors.

Controversy has, in fact, long waged as to whether centrally acting antlhypertenslve agents preferentially stimulate pre- or post-synaptlc alpha receptors

Although data from in vttro studies (e g isolated pulmonary artery, Starke et al , 1974) show the prefer- ential affinity of clomdlne for pertpheral pre-synaptic receptors, this is unimportant for the tn wvo antlhy- pertenslve effect Thus Haeusler (1976) found that in the anesthetized cat, stimulation of peripheral pre- synaptlc alpha adrenoreceptors (as judged by a reduc- tion in the stimulation-induced pressor response of the autoperfused hind quarters) occurred at relatively high doses (0 1 mg/kg 1 V ) of clonidine, whereas the antihypertenslve effect occurred at much lower doses

It has also been shown that clonldlne can stimulate cerebral-pre-synaptlc alpha adrenoreceptors for example, st was shown to block the outflow of nor- adrenaline from cerebral cortical shces m vitro (Starke & Montel, 1973) and to inhibit the spontaneous firing of the locus coeruleus neurons in the rat (Svensson et al , 1975) However in parallel with stimulation of peripheral pre-synaptlc receptors it appears that stimulation of cerebral pre-synaptic receptors is not essential for the antlhypertensive effect Thus, Haeusler & Finch (1972) showed that pretreatment with lntraventrlcular 6-hydroxydopamine (and hence destruction of central adrenerglc neurons and their pre-synaptlc receptors) did not modify the depressor effect of clonidine We would suggest that stimulation of cerebral pre-synaptlc receptors by centrally acting antlhypertensive agents is very important--not for their hypotenslve effect--but because it is by this mechanism that such agents can "turn off' the en- dogenous modulatory neurotransmltter system Thus single doses of clomdlne in rats have been shown to induce short-lived increases in noradrenahne concen- tration in various brain regions, including brainstem (Laverty & Taylor, 1969), due to feedback inhibition of noradrenahne release by stimulation of pre-synap- tic alpha adrenoreceptors Draper et al (1977) showed that decreased release of brain catecholamlnes could persist during chronic treatment They found that in rats treated for seven days with clonidlne the rate of decline of amine concentration after inhibition of syn- thesis was reduced presumably reflecting decreased amine release Decreased release could theoretically be followed by a decreased synthesis and turnover Rochette and coworkers (1974) showed that a single dose of clomdine (0 05 mg/kg i p ) decreased the rate of synthesis of noradrenahne in the rat brainstem by 50~o, and Tang and coworkers (1979) found that chro- nic clonidine treatment in rats induced a fall in total brain 3-methoxy-4-hydroxyphenylglycol (a major product of central nervous system noradrenahne turn- over) There was no tolerance to this effect Not all the evidence is in agreement with our theory, how- ever, for example, Kane & Johnson (1978) did not see any change in tyrosine hydroxylase (the rate-limiting step in catecholamlne synthesis) activity in locus coer- uleus of rats treated for 3 weeks with clonldlne

If we hypothesize that centrally acting antlhyper- tensive agents, by a combination of their pre- and post-synaptlc effects, not only modulate the activity of central cardiovascular centres (so as to reset them at a

lower blood pressure) but also replace and turn off the endogenous modulatory system, it is obvious that if the exogenous modulatory substance is suddenly unavailable the central cardiovascular modulatory system will be inactive until such a time as endogen- ous neurotransmltter synthesis is reinstored

It is known that destruction of modulatory centres in the brain can affect the cardiovascular system Thus bilateral destruction of the nucleus tractus soh- taru (the primary relay area for arterial baro- and chemoreceptor afferents) in the rat has been found to produce fulminating hypertension and death (Doba & Reis, 1973) Destruction of other modulatory centres such as A2 by either electrolytic lesions or mlcroinlec- tions of 6-hydroxydopamine induced increased blood pressure lability (possibly an early slgn of hyper- tension) but no change in mean arterial pressure (Reis et al , 1979) We would suggest that abrupt cessation of chromc treatment with centrally acting anti-hyper- tensive agents has a similar effect situated somewhere between these two extremes Hence withdrawal from varying schedules of chronic treatment with such agents could induce effects on blood pressure varying from mild increases in lability to fulminating hyper- tension

These changes in cardiovascular activity are pro- voked by increases in peripheral sympathetic nervous system activity which returns to normal once the cen- tral modulatory activity returns, itself, to normal The relative time course of these events is, obviously, very critical and we have as yet but little information on this

Dix & Johnson (1977) reported an increase in peri- pheral sympathetic activity as measured by tyroslne hydroxylase activity in adrenal glands, up to 80% above control levels 24 hr after withdrawal of clonl- dine Tyrosine hydroxylase remained elevated for 4 days, the effect was dependent on an intact pregangh- onic innervatlon and occurred at approximately the same time as the rebound tachycardia Other workers have reported contradictory data, for example, Prop (1978) reported a decrease in the tyrosine hydroxylase activity in the adrenal glands and no change in the central pontomedullary tyrosine hydroxylase activity without, however, stating at what time in relation to withdrawal, the measurements were made In contra- diction with the clinical data a dose-dependent rebound of plasma renin activity was reported by Oates and coworkers (1978) to occur when blood pressure and heart rate were elevated after withdrawal of clonldlne

Distefano and coworkers (1980) reported increased tyrosine hydroxylase activity in locus coeruleus and in adrenal glands, three days after the cessation of chro- nic treatment in normotensive rats which showed a rebound tachycardla at 30 hr after cessation of treat- ment Unfortunately they gave no figures for heart rate and blood pressure at three days following cessa- tion, i e coincident with their tyroslne hydroxylase measurements

Other studies have been done in which biochemical parameters have been measured with no attempt to correlate them with cardiovascular responses Tang et al (1979) reported an elevation of whole brain 3-methoxy-4-hydroxyphenylglycol (a noradrenahne metabohte) 28 hr and 48 hr after withdrawal of clonl-

Withdrawal symptoms from antlhypertenslve drugs 83

dine Total 3-methoxy-4-hydroxyphenylglycol was de- creased during clomdine t reatment Kane & Johnson (1978) found a 45~o decrease in 3-methoxy-4-hydroxy- phenylglycol in the celiac ganglion dur ing t reatment wtth clonldlne while there was no change in the superior cervical ganglion or the locus coeruleus They reported that tyrosine hydroxylase activity in- creased in the celiac and superior cervical ganglion 3-4 days after clonldlne withdrawal There was also an increase in the tyrosine hydroxylase activity in the locus coeruleus between 1 and 3 days after with- drawal which returned to control values after 8 days Svensson & St rombom (1977) have shown in mice that clonidlne decreases the formation of dopa and 5-hydroxytryptophan and that after withdrawal there was an accumulat ion of dopa in the hmbic system and brain stem (noradrenahne rich areas) and also a small increase of 5-hydroxytryptophan in the hmbic system These authors also demonst ra ted some sensit- ization of postsynaptic central alpha-adrenoreceptors following cessation of a low dose regime In a recent report Kmstler & Davis (1980) showed what appeared to be an increase in beta-receptor responsiveness In the brain stem 18 and 2 4 h r after clonidine with- drawal in the rat It would appear therefore, that chronic clonldlne t reatment lowers sympathetic ac- tivity in cerebral and extracerebral structures and that abrupt cessation of such t reatment provokes a rebound increase in sympathetic activity in bo th The temporal and causality relationships of these changes with those of the cardiovascular system must be further defined before our hypothesis can be either accepted or refuted

Recently, evidence has been provided showing that withdrawal phenomena following cessation of chronic t rea tment with centrally acting antlhypertenslve agents may not only involve the sympathetic nervous system interactions between centrally acting a lpha adrenoreceptor agonists, such as clonIdine, and opiates have been described

Clonldlne may have a r61e to play in opiate with- drawal Thus clonldlne has been shown to alleviate opiate withdrawal symptoms (Gold et a l , 1978a, 1978b, Uhde et a l , 1980) It has also been shown that morphine and clonidine act on (independent) recep- tors in the locus coeruleus to decrease neuronal firing rate, and, that clonidmne can suppress naloxone pre- cipitated neuronal firing of locus coeruleus cells in morphine-dependent rats (Aghajanlan, 1978) In ad- dit ion clonidlne prevented the increase in cortical 3-methoxy-4-hydroxyphenylglycol occurring during naloxone-preclpitated withdrawal (Crawley et a l , 1979, Laverty & Roth, 1980) It is interesting that piperoxane, an a lpha receptor antagonist which blocks the actions of clonldlne, has been shown to accelerate firing of locus coeruleus neurones and pro- duce symptoms of anxiety and hypertension (Red- mond, 1977) reminiscent of those seen after opiate and clonidlne withdrawal

Clonldlne has been shown to have analgesic properties and Lln et al (1980) have proposed that the modula t ion of bo th clonmdme and fl-endorphln analgesia may pass in part th rough the same seroto- nergic pathways Farsang & Kunos (1979) reported that naloxone would inhibit the decrease in blood pressure and heart rate produced by clonldine in un-

anesthettzed spontaneously hypertensive rats, and suggested that release of an endogenous opmte by clonldlne is one possible way in which the cardio- vascular effects of clonidine are mediated Finally Thoolen & coworkers (1981) showed that morphine will block the overshoot tachycardla and blood press- ure upswings occurring upon clomdlne withdrawal (naloxone, however, was without effect)

REFERENCES

ABERNETHV J D (1974) The Austrahan national blood pressure study Med J Aust 1, 821-824

AGHAJANIAN G K (1978) Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidlne Nature 276, 186-188

ALLEN R & GENOVESE B (1975) Propranolol withdrawal Ann intern Med 82, 431

ATKINSON J, BOILLAT N, PERA-BALLY R, PETERS-HAEFELI L & KIRCHERTZ E J (1979) Effect of chronic clomdme treatment and its abrupt cessation on mean blood press- ure of rats with a normal or an elevated blood pressure Chn ScI 57, 195-201

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