Comparison of the effects of clonidine on tyramine‐ and methoxamine‐evoked mydriasis in man

Abstract

1 It has been reported previously that clonidine can potentiate tyramine‐evoked mydriasis on the pain‐free side of cluster headache patients. We examined whether a single oral dose of clonidine (200 μg) can also potentiate tyramine‐evoked mydriasis in healthy subjects, using mydriasis to methoxamine, a directly acting sympathomimetic amine, as a control. 2 Eight healthy male volunteers participated in four weekly sessions. In the first two sessions (Experiment 1) the effect of clonidine or placebo on the mydriasis to tyramine hydrochloride eyedrops (75 mm; 2×10 μl), and in the last two sessions (Experiment 2) the effect of clonidine or placebo on the mydriasis to methoxamine hydrochloride eyedrops (20 mm; 2×10 μl) was examined. In both experiments subjects were allocated to drugs and sessions according to a double‐blind balanced design. In both experiments, pupil diameter of both the treated and the untreated eyes was recorded in standard ambient light and in the dark, before, and 2 h after clonidine/placebo, via binocular infrared television pupillometry. Salivation (dental roll technique), systolic and diastolic blood pressure (sitting), heart rate, and self‐ratings of mood and feelings (visual analogue scales), were also measured before, and 2 h after the ingestion of clonidine or placebo. 3 Both tyramine and methoxamine produced a significant mydriasis, which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: tyramine/light 1.05±0.28; tyramine/dark: 0.73±0.15; methoxamine/light: 1.65±0.28; methoxamine/dark: 0.85±0.15). Clonidine produced a significant miosis in the untreated eye which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: Experiment 1, light: −1.34±0.19; Experiment 1, dark: −0.46±0.1; Experiment 2, light −0.97±0.18; Experiment 2, dark: −0.29±0.17). Clonidine had no significant effect on either tyramine‐ or methoxamine‐evoked mydriasis. 4 In agreement with previous reports, clonidine significantly reduced salivation (g, mean±s.e.mean; Experiment 1: −0.84±0.22; Experiment 2: −0.55±0.11), systolic blood pressure (mm Hg; Experiment 1: −17.5±3.76; Experiment 2: −23.38±4.67), diastolic blood pressure (mm Hg; Experiment 2: −12.38±2.05), alertness (mm; Experiment 2: −24.19±5.40), and anxiety (mm; Experiment 1: −13.82±4.60), indicating the presence of pharmacodynamically effective tissue levels of the drug. 5 These results show that a single oral dose (200 μg) of clonidine causes significant miosis in human subjects, and fails to potentiate tyramine‐evoked mydriasis. This indicates that the pupil on the asymptomatic side of cluster headache patients is affected differently from the pupils of healthy volunteers by tyramine and/or clonidine.

Comparison of the effects of clonidine and yohimbine on spontaneous pupillary fluctuations in healthy human volunteers

“…In the present experiment, clonidine had no effect on resting pupil diameter, in agreement with earlier reports that the drug has no (Morley et al 1991) or little (Bitsios et al 1996) effect when pupil size is recorded in the dark. However, a miotic effect of clonidine has been described when pupil diameter is measured in an illuminated environment (Clifford et al 1982(Clifford et al , 1989Fanciullacci et al 1988;Bitsios et al 1996Bitsios et al , 1998.…”

“…The reduction in salivation evoked by clonidine can be interpreted as reflecting the stimulation of inhibitory α 2 -adrenoceptors located on preganglionic parasympathetic salivatory neurones in the lower brainstem, whereas the effect of yohimbine could be due to the blockade of the same receptors Tavernor 1999). Clonidine decreased subjectively rated alertness, in agreement with previous reports (Morley et al 1991;Bitsios et al 1996Bitsios et al , 1998Abduljawad et al 1997). The sedative effect of clonidine is well documented in the literature, both in experimental animals (Drew et al 1979;Strombom and Svensson 1980;Lal and Shearman 1981) and in human subjects (Lal and Shearman 1981;Glue and Nutt 1988).…”

Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

“…Clonidine reduced pupil diameter (Bitsios et al, 1996;Phillips et al, 2000c, d;Hou et al, 2005, reduced systolic and diastolic blood pressure in both the supine and the standing positions (Lal et al, 1975;Berlan et al, 1989;Morley et al, 1991;Bitsios et al, 1996;Kumari et al, 1996;Abduljawad et al, 1997Abduljawad et al, , 2001Arya et al, 1997;Phillips et al, 2000d;Hou et al, 2005, reduced salivation (Bitsios et al, 1996;Abduljawad et al, 1997Abduljawad et al, , 2001Arya et al, 1997;Phillips et al, 2000d;Hou et al, 2005, and reduced core temperature (Arya et al, 1997;) (see Figure 5 and Table 2). The autonomic effects of clonidine are consistent with the stimulation of inhibitory a 2 -adrenoceptors on central neurons.…”

“…The doses were chosen on the basis of the current literature (modafinil: Taneja et al, 2005;clonidine: Morley et al, 1991;Bitsios et al, 1996;Phillips et al, 2000c, d). The time required to attain peak plasma concentrations (t MAX ) of clonidine and modafinil after the ingestion of single doses is approximately 2 h (modafinil: Wong et al, 1998;clonidine: Lowenthal et al, 1988), and the time course of the sessions was designed to ensure peak plasma concentrations of the drugs at the start of the post-treatment testing.…”

Comparison of the effects of high ambient temperature and clonidine on autonomic functions in man

“…Since in a previous study we found that the anxiolytic drug diazepam can reduce sweat gland activation by carbachol only at high ambient temperature (Banjar et al 1987), when sympathetic activity is expected to be increased, it is possible that a potential suppressant effect of clonidine on finger tremor may become apparent only at higher levels of sympathetic activity. Indeed, there is some evidence that the effect of clonidine on some autonomic functions may be "baseline-dependent": clonidine fails to reduce heart rate in supine subjects when the sympathetic drive to the heart is presumably low (Muzi et al 1992), and its miotic effect is more pronounced at higher illumination levels (Bitsios et al 1996) when the parasympathetic drive to the iris is likely to be higher . Therefore, we decided to re-examine the effect of clonidine on physiological finger tremor at high ambient temperature which is known to enhance both sympathetic activity (Bini et al 1980) and finger tremor (Al-Eithan et al 1991).…”