Clonidine and apraclonidine

Observational studies

The antihypertensive action of clonidine is attributed to its central action as an α ₂ adrenoceptor agonist, although this assumption may not explain all of its antihypertensive actions. In an experimental study of the hemodynamic response to clonidine in 28 young healthy men, the hemodynamic response suggested that the hypotensive action of clonidine is caused by both an immediate reduction in peripheral vascular resistance and a prolonged reduction in cardiac output [ ]. The study also showed that central blood pressure was reduced more than peripheral blood pressure, according to pulse wave velocity indices.

Cardiovascular

Clonidine causes sinus bradycardia and atrioventricular block, as illustrated by two cases, one a 10-year-old boy [ ] and the other a 71-year-old woman [ ], who developed Wenckebach’s phenomenon. Clonidine was also studied in seven patients subjected to electrophysiological studies after 5 weeks of therapy [ ]. It slowed the sinus rate and increased the atrial pacing rate, producing Wenckebach’s phenomenon, indicating depressed function of the sinus and AV nodes.

In three patients with chronic schizophrenia and primary polydipsia given clonidine in doses of up to 800 micrograms/day for 2–5 months, blood pressure and pulse fell significantly in a dose-dependent manner, but fluid intake, as assessed by measurements of weight and 24-hour urine volume, was not affected [ ]. Hypotension and bradycardia limited the extent to which the dose of clonidine could be increased. The lack of effect of clonidine on polydipsia in this small sample and the inconsistent results of two other recent studies have provided little overall support for using clonidine to treat primary polydipsia associated with schizophrenia.

Clonidine-induced hypertension has been reported in a patient with autonomic dysfunction [ ].

• A 39-year-old quadriplegic man with poorly controlled pain had many features consistent with autonomic dysfunction (for example a C4 spinal lesion, orthostatic hypotension, hypertension). He routinely used transdermal clonidine and transdermal glyceryl trinitrate as needed for control of acute hypertensive episodes. The clonidine was discontinued, after which his blood pressure fell (maximum systolic and diastolic pressures by about 50 and 25 mmHg respectively).

Because clonidine relies on central α ₂ -adrenoceptor agonist activity for its hypotensive effects, it can cause hypertension in patients with autonomic dysfunction. It should therefore be used with great caution when autonomic dysfunction is suspected.

The effect of intrathecal clonidine has been evaluated in a prospective randomized study in 45 children aged 6–15 years, who were randomized to receive either 0.5% hyperbaric bupivacaine or 0.5% hyperbaric bupivacaine plus clonidine 2 micrograms/kg [ ]. Clonidine was associated with non-significant prolongation of motor block, from an average of 150–190 minutes. Postoperative analgesia was significantly longer with clonidine (490 versus 200 minutes). Clonidine was associated with higher incidences of hypotension (54% versus 36%) and bradycardia (30% versus 0%).

Respiratory

The effects of clonidine and other α ₂ -adrenoceptor agonists on respiratory function in asthmatics have been reviewed [ ]. Inhaled α ₂ -adrenoceptor agonists reduce the bronchial response to allergens, and if ingested they can aggravate the bronchial response to histamine.

Nervous system

Treatment with centrally acting agents is characterized by a relatively high incidence (up to 60% in some studies) of nervous system depressant effects (dizziness, drowsiness, tiredness, dry mouth, headache, depression), particularly during the initial period of treatment or after dosage increments. Sedation, lethargy, and tiredness are common with clonidine, particularly at the start of treatment [ ].

In a placebo-controlled study of a single oral dose of clonidine 0.25–3 mg in 18 healthy men aged 18–21 years, clonidine caused more sleepiness than placebo; it significantly reduced stage 1 and rapid-eye-movement (REM) sleep and increased stage 2 sleep [ ].

Clonidine 300 micrograms was given orally to 30 patients 60 minutes before intrathecal anesthesia with lidocaine 40 mg or 80 mg, and 60 mg other patients received either plain lidocaine 100 mg or lidocaine 40 mg or 80 mg with clonidine 100 micrograms intrathecally [ ]. Clonidine, both intrathecally and orally, prolonged the duration of spinal block and allowed a reduction in the dose of lidocaine needed for a given duration of block, but prolongation of motor block, exceeding the duration of sensory block, was a drawback with both routes and doses of clonidine. The smallest hemodynamic changes were seen with lidocaine 40 mg + clonidine 100 micrograms intrathecally, which provided adequate anesthesia for operations lasting up to 140 minutes. All doses of clonidine caused sedation.

The electroencephalographic effects of clonidine have been reported [ ]. There was electrophysiological sedation after parenteral clonidine, an effect that the authors concluded was likely to relate to the drug’s analgesic properties rather than direct modulation of the nociceptive system.

Anecdotal reports have shown that clonidine can induce epileptic activity. In 22 patients with chronic, medically intractable, localization-related epilepsy, magnetoencephalography was used to investigate whether oral clonidine can aid localization of spike or sharp-wave activity as well as to gain knowledge about whether clonidine is epileptogenic [ ]. Oral clonidine-induced magnetoencephalographic activity was superior to sleep deprivation, and therefore may be an aid to localization as well as showing epileptogenic activity.

Endocrine

Clonidine stimulates the release of growth hormone and has been used as a provocation test of growth hormone reserve [ ].

Clonidine reduces plasma renin activity and urinary aldosterone and catecholamine concentrations [ ].