Clonidine sedative effects

The sedative effects of clonidine were observed in the very first animal experiments performed (HOEFKE and KOBINGER (11)). Obvious symptoms of sedation can be observed on administration of therapeutic doses to dogs, cats, rabbits, rats and mice. Investigations on the mechanism of the sedative action have mainly been performed on chicks. In chicks only a couple of days old the blood-brain barrier is not yet fully developed. 

Noradrenaline is the neurotransmitter most closely associated with the peripheral and central stress response (Figure 9.5). There is experimental evidence to show that drugs such as yohimbine that block the noradrenergic autoreceptors (e.g. on cell bodies and nerve terminals) and thereby enhance noradrenaline release cause fear and anxiety in both man and animals. Conversely, drugs that stimulate these autoreceptors (as exemplified by clonidine) diminish the anxiety state because they reduce the release of noradrenaline. Benzodiazepines have been shown to inhibit the fear-motivated increase in the functional activity of noradrenaline in experimental animals, but it is now widely believed that the action of the benzodiazepines on the central noradrenergic system is only short term and may contribute to the sedative effects which most conventional benzodiazepines produce, at least initially. Nevertheless, altered noradrenergic... 

By activating presynaptic autoreceptors in brain stem locus ceruleus neurons (where most noradrenergic fibers have their origin), clonidine reduces norepine-pherine release and turnover. This inhibitory effect on noradrenergic locus ceruleus neurons, as well as direct effects on thalamic receptors, are most likely responsible for the sedative effects of clonidine (Berridge and Foote, 1991 Buzsaki et ah, 1991). 

CENTRALLY ACTING ANTIHYPERTENSIVES ALCOHOL Clonidine and moxonidine may exacerbate the sedative effects of alcohol, particularly during initiation of therapy Uncertain Warn patients of this effect and advise them to avoid driving or operating machinery if they suffer from sedation... 

TCAs CENTRALLY ACTING ANTI HYPERTENSIVES 1. Possibly hypotensive effect of clonidine and moxonidine antagonized by TCAs (some case reports of hypertensive crisis). 2. Conversely, clonidine and moxonidine may exacerbate the sedative effects of TCAs, particularly during initiation of therapy 3. Methyidopa may i effect of antidepressants 1 and 2. Uncertain 3. Methyidopa can cause depression 1. Monitor BP at least weekly until stable 2. Warn patients of the risk of sedation and advise them to avoid driving or operating machinery if they suffer from sedation. 3. Methyidopa should be avoided in patients with depression... 

A study in a group of 10 women found that the sedative effects of a single 1.3-microgram/kg dose of intravenous clonidine were increased by a combined oral contraceptive (ethinylestradiol/levonorgestrel 30 micrograms/150 or 250 micrograms). The clinical importance of this is uncertain. Consider also Antihypertensives + Hormonal contraceptives ,... 

Common adverse events clonidine has a centrally mediated sedative effect. Other CNS depressants, such as benzodiazepines and opioids, may enhance the sedative effects of clonidine. Neuraxial clonidine can also affect the sympathetic nervous system, resulting in hypotension and bradycardia. When clonidine is used as a neuraxial adjunct analgesic, its hemodynamic effects may be enhanced by other neuraxial medications, particularly as local anesthetics. AU effects are dose- dependent. 

In mice with mutations in the a2A-receptor gene it was established that the a2A subtype mediates the analgesic and anesthesia-sparing effects of clonidine and dexmedetomidine, but unfortunately also the sedative and vasodepressor effects of these drugs (Lakhlani et al., 1997). Thus, it seems unlikely that new subtype-selective compounds will lack the major side-effects of the existing drugs. 

Clonidine hydrochloride has advantages over antihyper-icnsive drugs such asguanethidinc monosulfate and prazosin hydrochloride, in that it seldom produces orthostatic hypo-icndvc side effects. It does, however, have some sedative properties that ate undesirable it also may cau.se constipa-ilnn and dryness of the mouth. 

Chalmers JS,Fulli-Lemaire I, CowenPJ. Effects ofthe contraceptive pill on sedative responses to clonidine and apomorphine in normal women. PsycholMed (1985) 15, 363-7. 

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