Withdrawal of guanfacine after long-term treatment in essential hypertension

Abstract

1. Guanfacine (2-6 mg/day) a centrally acting antihypertensive drug, was effective in controlling blood pressure in 5 essential hypertensives and lowered plasma noradrenaline and urinary catecholamine excretion. 2. Withdrawal of guanfacine by blind substitution of identical placebo tablets under observation in hospital led to a gradual recovery of blood pressure over 2-4 days. 3. Salivary flow, which was reduced on guanfacine, returned to pretreatment levels by 2 days after withdrawal and significantly exceeded control for the next two days. 4. Urinary catecholamine excretion returned to pretreatment levels by 3 days but did not exceed control levels during the period of study. 5. Plasma noradrenaline returned gradually to pretreatment levels, and by day 4 significantly exceeded them. 6. No patient experienced symptoms suggesting catecholamine excess although four out of five reported a headache from the second day onwards. 7. Guanfacine, a centrally acting drug which pharmacologically resembles clonidine, has a slow offset of hypotensive effect over 2-3 days. Symptoms or biochemical evidence of catecholamine excess were not encountered within 48 h of withdrawal, possibly reflecting the longer duration of action and plasma half-life of guanfacine.

The Fourth Lilly Prize Lecture, University of Aberdeen, September 1980. The clinical pharmacology of clonidine and related central antihypertensive agents.

“…Guanfacine which as noted earlier has a longer plasma half-life and duration of action after single doses, had a slower offset of action on withdrawal and less subjective symptoms. However, guanfacine has also been reported to cause withdrawal hypertension (Jerie, 1980) and 3-4 days after withdrawal plasma noradrenaline was significantly higher than pretreatment levels (Zamboulis & Reid, 1981). These latter results suggest that while withdrawal symptoms may be a general feature of centrally acting drugs, differences in drug disposition and especially prolongation of drug action may modify the intensity and severity of these effects.…”

“…(Draffan et al, 1975;Dollery et al, 1976 There is less information available on the pharmacokinetics of other imidazoline derivatives. Tiamenidine has a similar half life to clonidine but guanfacine has a longer half life ranging from 15 to over 30 h (Zamboulis & Reid, 1981). The relevance of these kinetic differences remains to be established and can only be fully explored when the time course of dynamic effects is also considered.…”

Effects of clonidine and guanfacine in essential hypertension

“…A washout period of 3 days was kept between treatments, since parameters returned to pretreatment levels within 2 to 4 days after abrupt withdrawal of guanfacine, the drug with the longer duration of action.'3. 53, s43 59 The ratio of the equiactive antihypertensive dose of guanfacine : clonidine of 10 : 1 was selected on the basis of the literat~re.~.…”

“…It is established that the antihypertensive effects of clonidine and guanfacine involve the activation of a,-adrenergic receptors in the central nervous system (CNS) and are a consequence of reduced sympathetic tone.z0, 493 5s Despite the similar mode of action of clonidine and guanfacine, however, there are important differences. The duration of action of guanfacine (t% = 21 hr) is longer than that of clonidine (8.5 hr), and rebound sympathetic overactivity during guanfacine withdrawal is rare, whereas it is more frequent after cessation of clonidine therapy.8, z43 463 53,54,59 On the basis of differences between the effects of clonidine and guanfacine, we presumed only some may be ascribed to the involvement of endogenous opioid(s) in the action of clonidine. Our findings appear to support such a hypothesis.…”

The Pharmacology of Centrally Acting Antihypertensive Drugs

“…(1) clonidine may cause withdrawal phenomena upon sudden cessation of antihypertensive therapy; (2) guanfacine causes withdrawal phenomena infrequently and to a modest and clinically irrelevant degree (Thoolen et al, 1982;Zamboulis & Reid, 1981); (3) a-methyldopa has been reported to cause withdrawal phenomena in humans only in exceptional cases and in animal experiments this drug does not cause withdrawal phenomena (Thoolen et al, 1983).…”