Clonidine (Catapresan) interaction with tricyclic antidepressants and other CNS-active/ndrugs? Warn

Fråga: Clonidine (Catapresan) interaction with tricyclic antidepressants and other CNS-active

drugs? Warnings circulate - how great is the risk, how strong is the documentation?

Sammanfattning: Antagonism of the hypotensive effects of clonidine has been demonstrated with

concomitant administration of desipramine. This interaction has also been described for

imipramine in case reports. No other adverse effects have been described as a result of an

interaction between clonidine and these tricyclic antidepressants. Although a number of other

interactions between clonidine and neuroleptics and an opioid antagonist have been

described, the documentation is scarce and based on either animal studies or anecdotal

reports. Thus there is presently no documentation to contraindicate the combination of

clonidine and tricyclics or other psychotropic drugs. However, the effect of concomitant

psychotropic drugs on clonidine action in opioid withdrawal has not been evaluated.

Svar: A number of central nervous system-acting drugs have been reported to interact with

clonidine.

The tricyclic antidepressant drugs desipramine and imipramine are known to antagonize the

hypotensive effects of clonidine. In a double blind trial, four of five hypertensive patients on

chronic clonidine therapy presented rises in blood pressure (average of 22/15 mmHg on lying

and 12/11 mmHg when standing) when desipramine was also taken, but not during placebo

(1). In a study of depressed patients, it was shown that the hypotensive effects of single

infusions of clonidine were inhibited by desipramine (three weeks of previous treatment

compared to pretreatment response to clonidine) in all six patients (2). Imipramine is

metabolized to desipramine and there have been case reports of an imipramine interaction

with clonidine (3-5).

The mechanism for this interaction has not yet been elucidated. Animal studies suggest that

the interaction involves the alpha-2-adrenergic system and occurs in the brain, although

involvement of peripheral adrenergic neurons cannot be excluded (6). Imipramine and

amitriptyline were shown to antagonize slightly the effects of clonidine in anesthetized cats

(7). In a study involving eight healthy volunteers, maprotiline, a tetracyclic antidepressant and

potent inhibitor of noradrenaline uptake, was found not to interact with clonidine (8),

suggesting that blockade of noradrenaline uptake is not involved in the interaction between

tricyclic antidepressants and clonidine.

Neuroleptics have also been reported to interact with clonidine. Severe hypotension has been

reported with concurrent administration of clonidine and chlorpromazine in one patient, and

clonidine with haloperidol in another (9). However, the severe hypotension could also have

resulted from concomitant administration of furosemide in the first case, and excessive

dosage in an 88-year-old patient in the second case. Moreover, these single case findings are

in contrast to animal studies that show an antagonistic effect of neuroleptics (chlorpromazine,

promazine, promethazine, thiethylperazine, thioridazine, chlorprothixene, and haloperidol) on

the hypotensive effect of clonidine (10).

An organic brain syndrome (delirium, clouded consciousness, agitation) has been reported in

a patient on clonidine and chlorthalidone treatment who was given fluphenazine. The

symptoms disappeared when clonidine was discontinued, but reappeared upon rechallenge

with clonidine (11).

Naloxone, an opiod antagonist, has been reported to reverse the coma and apnea in a

16-month-old child who had ingested an unknown quantity of clonidine (12). Naloxone has

also been shown to reverse the antihypertensive effect of clonidine in rats (13). 1 Briant RH, Reid JL, Dollery CT: Interaction between clonidine and desipramine in

man. Br Med J 1973; 1: 522-523
2 Checkley SA, Slade AP, Shur E, Dawling S: A pilot study of the mechanism of action of
desipramine. Br J Psychiatry 1981; 138: 248-251
3 Conolly ME, Paterson JW, Dollery CT. In: Conolly ME (ed) Catapres in hypertension.
London: Butterworth´s Publishing, 1969 (cited in Stockley I, Drug interactions. Oxford,
Blackwell Scientific Publications, 1981, p 226)
4 Coffler DE: Antipsychotic drug interaction. Drug Intell Clin Pharm 1976; 10: 114-115
5 Hui KK: Hypertensive crisis induced by interaction of clonidine with imipramine. J Am
Geriatr Soc 1983; 31: 164-165
6 Stockley I: Drug interactons. Oxford Blackwell Scientific Publications, 1981, p 226
7 Schmitt H, Schmitt H, Fenard S: Action of alpha-adrenergic blocking drugs on the
sympathetic centres and their interactions with the central sympatho-inhibitory effect of
clonidine. Arzneim Forsch 1973; 23: 40-45
8 Gundert-Remy U, Amann E, Hildebrandt R, Weber E: Lack of interaction between the
tetracyclic antidepressant maprotiline and the centrally acting antihypertensive drug clonidine.
Eur J Clin Pharmacol 1983; 25: 595-599
9 Fruncillo RJ, Gibbons WJ, Vlasses PH, Ferguson RK: Severe hypotension associated with
concurrent clonidine and antipsychotic medication. Am J Psychiatry 1985; 142: 274
10 van Zwieten PA: The interaction between clonidine and various neuroleptic agents and
some benzodiazepine tranquilizers. J Pharm Pharmacol 1977; 29: 229-234
11 Allen RM, Flemenbaum A: Delirium associated with combined fluphenazine-clonidine
therapy. J Clin Psychiatry 1979; 40: 236 (cited in APhA, Evaluations of drug interactions,
1985; 3rd ed: 450)
12 Kulik K, Duffy J, Rumack BH, Mauro R, Gaylord M: Naloxone for treatment of clonidine
overdose. JAMA 1982; 247: 1697
13 Farsang C, Kunos G: Naloxone reverses the antihypertensive effect of clonidine. Br J

Pharmacol 1979; 67: 161-164