Noradrenaline Clonidine

The fact that the modes of action of clonidine and a-methylnoradrenaline are similar to the mode of action of the physiological transmitter noradrenaline indicates the importance of the role of the latter in the central control of blood pressure. It may be mentioned that 1-dopa too, the precursor of noradrenaline, penetrates the blood-brain barrier and causes hypotension and bradycardia after systemic administration, when do-... 

Recent experiments carried out by BOLME and coworkers (39) now raise the question of whether the receptors involved in reducing blood pressure are epinephrine receptors or noradrenaline receptors. These workers found that in rats small doses of yohimbine and piper-oxan blocked the blood pressure lowering effect of clonidine, but did not influence the clonidine-induced increase in flexor reflex activity. This effect on the reflex mechanism is possibly mediated by noradrenaline receptors which can be blocked only by higher doses of a-adrenolytic agents. HtfKFELT et al. (40) consider that epinephrine terminals possibly innervate noradrenaline cell bodies at the locus coeruleus. 

Besides the similar biological properties of noradrenaline, clonidine and other imadazoline compounds there are also similarities in the molecular structure (fig. 11). I have taken noradrenaline as an example of a substance acting on a-receptors. According to PULMAN et al. (43), two distances in the molecule are predominant. A distance D from the cationic centre N+ to the centre of the aromatic ring equals 5.1 - 5.2 8 and a... 

Figure 11. Appropriate structures of clonidine and noradrenaline for interaction with the postulated a-adrenergic receptors (on the basis of data from (43) and...

This means that even substances administered to the periphery of the body display an effect on the CNS which can no longer be observed later on. Clonidine induces sleep in these animals, as described by ZAIMIS (49), FUGNER and HOEFKE (50) and by DELBARRE and SCHMITT (51). Noradrenaline, as well as a-methylnoradrenaline, which cannot permeate the blood-brain barrier in older animals, cause sleep. This effect could be inhibited with phentolamine in the case of noradrenaline and also in the case of clonidine (FUGNER (52)). Therefore it may be assumed, that here again central adrenergic alpha-receptors are involved. 

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... 

Noradrenergic neurons at the locus coeruleus and serotonergic neurons at the raphe dorsalis complex project to the brain cortex and may play a role in AD. Drugs that raise serotonin levels, such as imipramine or zimeldine or a noradrenaline such as clonidine or guanfacine, have been used in AD [Mohr et al. 1989). Again, another chapter of this book deals with this aspect. 

Tricyclic antidepressants potentiate the pressor effects of directly acting sympathomimetic amines, such as adrenaline (epinephrine) or noradrenaline (norepinephrine), to cause hypertension. Small amounts of these, such as may be present in local anaesthetic solutions, can be dangerous. Tricyclic antidepressants will inhibit the antihypertensive effects of the older anti hypertensive drugs, such as adrenergic neurone-blocking agents, e.g. guanethidine, a-methyl-DOPA, and clonidine. 

In this chapter, we have looked at two topics in cognitive enhancement attention and memory. We have first reviewed the role of dopamine and norepinephrine/ noradrenaline in the neuropharmacology of attention, and then the syndrome of attention deficit disorder as a common problem associated with a disorder of attention. We then discussed the use of stimulants for improving attention, primarily in attention deficit disorder, and reviewed the pharmacological mechanisms of action of methylphenidate, d and 1 amphetamine, pemoline, and secondary therapies such as clonidine and guanfacine. 

Svensson TH, Usdin T (1978) Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants a-receptor mediation. Science 202 1089-91 Svensson TH, Bunney BS, Aghajanian G (1975) Inhibition of both noradrenergic and serotonergic neurons in the brain by the a-adrenergic agonist clonidine. Brain Res 92 291-306 Szabo B (2002) Imidazoline antihypertensive drugs a critical review on their mechanism of action. Pharmacol Therapeut, 93 1-35... 

In 12 patients clonidine 50-100 micrograms/day relieved clozapine-induced sialorrhea, with good results in three and partial results in eight (178). Theoretically, the reduction in sialorrhea with clonidine could have been due to reduced plasma noradrenaline concentrations, resulting in less stimulation of unopposed p-adrenoceptors in the salivary glands. 

Clonidine (Catapres) is an imidazoline which is an agonist to ctj-adrenoceptors (postsynaptic) in the brain, stimulation of which suppresses S5unpathetic outflow and reduces blood pressure. At high doses it also activates peripheral a -adrenoceptors (pre-synaptic autoreceptors) on the adrenergic nerve ending these mediate negative feedback suppression of noradrenaline release. In overdose clonidine can stimulate peripheral Oj-adrenoceptors (postsynaptic) and thus cause hypertension by vasoconstriction. Clonidine was discovered to be hypotensive, not by the pharmacologists who tested it in the laboratory but by a physician who used it on himself as nose drops for a common cold. The tl is 6 h. 

Methyldopa (Aldomet) probably acts primarily in the brain stem vasomotor centres. It is a substrate (in the same manner as L-DOPA) for the enzymes that synthesise noradrenaline. The synthesis of cx-methylnoradrenaline results in tonic stimulation of CNS oCj-receptors since a-methylnoradrenaline cannot be metabolised by monoamine oxidase, and selectively stimulates the Oj-adrenoceptor. Stimulation of this receptor in the hindbrain nuclei concerned with blood pressure control results in a fall in blood pressure, i.e. methyldopa acts in the same way as clonidine. a-Methylnoradrenaline is also produced at peripheral adrenergic endings, but to a lesser extent and peripheral action is clinically insignificant. 

Central mechanisms. Some agents may act within the CNS to modify autonomic control of sympathetic tone and blood pressure. Clonidine inhibits release of noradrenaline by an agonist action at the autoinhibitory a2-adrenoceptors on sympathetic nerve endings. Methyldopa is thought to work, at least in part, centrally, acting both as an inhibitory false substrate in the biosynthetic pathway, also producing an active metabolite with actions at aj-adrenoceptors. 

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