Clonidine Norepinephrine

Clonidine (Catapres). Like the beta blockers, clonidine acts by reducing norepinephrine activity, though by a different mechanism. Studies show that clonidine can provide early relief from the symptoms of a panic attack, but patients unfortunately relapse with continued treatment. Therefore, clonidine is not used in the treatment of panic disorder. 

Other agents, clonidine and guanfacine, reduce norepinephrine activity by reducing its release. Open label studies suggest these agents might be helpful for the impulsivity that often accompanies PTSD, but the lone controlled study did not find guanfacine to be effective. 

Clonidine (Catapres). Clonidine is largely used to treat high blood pressure. Although we don t fully understand how clonidine acts, it appears to reduce norepinephrine activity by stimulating a norepinephrine receptor known as the alpha-2 receptor. When clonidine binds to alpha-2 receptors on norepinephrine neurons, so-called autoreceptors, the cells are tricked into believing that there is already sufficient norepinephrine released and thus decrease any additional release of norepinephrine. As one might anticipate, clonidine is somewhat effective at reducing the hyperactivity and impulsivity of ADHD. It does not, however, provide nearly as much benefit for the inattention of ADHD. 

A host of medications have been nsed to treat TD including medications that block norepinephrine activity (clonidine and propranolol), dopamine-activating medications (bromocriptine), benzodiazepines, acetylcholine-activating medications, calcium channel blockers, and monoamine oxidase inhibitors. In addition, vitamin E supplementation and atypical antipsychotics including clozapine have been used to treat TD. 

Uses Endogenous depression Action TCA T synaptic CNS levels of serotonin /or norepinephrine Dose Adults. 25 mg PO tid-qid >150 mg/d not OK Elderly. 10-25 mg hs Peds. 6-7 y 10 mg/d 8-11 y 10-20 mg/d >11 y 25-35 mg/d, 4- w/ hepatic insuff Caution [D, +/-] NAG, CV Dz Contra TCA allergy, use w/ MAOI Disp Caps, soln SE Anticholinergic (blurred vision, retention, xerostomia) Interactions T Effects W/ antihistamines, CNS depressants, cimetidine, fluoxetine, OCP, phenothiazine, quinidine, EtOH T effects OF anticoagulants T risk of HTN W/clonidine, levodopa, sympathomimetics T effects W/barbiturates, carbamazepine, rifampin EMS Concurrent use w/ MAOIs have resulted in HTN,... 

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. 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the central nervous system to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery. However, it may increase blood pressure in some patients. Norepinephrine reuptake is particularly important in the heart, particularly during sympathetic stimulation, and this... 

Thus, studies of clonidine and methyldopa suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and a-methylnorepinephrine bind more tightly to a2 than to adrenoceptors. As noted in Chapter 6, a2 receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and -methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic a2 adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects. 

Clonidine, methyldopa Activate K-2 adrenoceptors Reduce central sympathetic outflow reduce norepinephrine release from noradrenergic nerve endings Hypertension clonidine also used in withdrawal from abused drugs Oral t clonidine also patch Toxicity sedation t methyldopa hemolytic anemia... 

FIGURE 8—13. If an alpha 2 agonist such as clonidine, is administered, it will have much the same action as norepinephrine (NE) itself both at somatodendritic alpha 2 autoreceptors and at terminal alpha 2 autoreceptors. This action is that of reducing both neuronal impulse in NE neurons and release of NE from noradrenergic axon terminals. Thus, alpha 2 agonists will decrease the symptoms associated with anxiety, especially the autonomic symptoms of dilated pupils, tachycardia, tremor, and sweating. 

FIGURE 12-6. Postsynaptic alpha 2 adrenergic receptors are postulated to mediate cognitive effects of norepinephrine in the frontal cortex. Direct-acting alpha 2 agonists such as clonidine and guanfacine can be helpful in attention deficit disorder, perhaps because of actions at this site. 

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. 

In the early 1970s, it was accepted that the hypotensive activity of clonidine was due to its direct interaction with the central norepinephrine receptor [26]. To trigger the a-adrenergic receptor, it was accepted that norepinephrine binds to its receptor by means of three bonds [27, 28] ... 

Fig. 1.4 In clonidine (B) the restricted rotation resulting from o- and o -substitution imposes a quasi-perpendicular orientation of the imidazolic ring towards the phenyl ring. As a result, clonidine can yield the same kind of interactions than norepinephrine (A).

Another dmg closely similar to DOPA but used for different applications is a-methyl-DOPA (Figure 10.19a). This molecule acts in the peripheral autonomous system but also enters the brain, by the same route as DOPA. It is converted by DOPA decarboxylase to the false transmitter a-methyl-dopamine. Like dopamine or norepinephrine, a-methyl-dopamine is accumulated inside the transmitter vesicles, and released in response to action potentials. While it has no strong effect on postsynaptic a,-receptors, it does activate 0C2-receptors. It will therefore inhibit the further release of transmitter without stimulating the postsynaptic neuron. The effect of methyl-DOPA is augmented by the fact that it is fairly resistant to monoamine oxidase. Its mode of action resembles that of clonidine (which accomplishes the same in a less roundabout manner). 

A clinical review of clonidine (1984—1995). Anesthesiology 85 655-674 Eisenach JC, Detweiler DJ, Tong C, D Angelo R, Hood DD (1996b) Cerebrospinal fluid norepinephrine and acetylcholine concentrations during acute pain. Anesth Analg 82 621-626... 

Clonidine (Catapres) is an alpha-2 adrenergic agonist, which thereby functions as a presynaptic irdiibitor of norepinephrine release. It is usually used to treat hypertension (like the beta blockers) but has been used to treat amciety disorders with some success. It is also used to treat opiate withdrawal. A typical starting dose is 0.1 mg two to three times daily (see figure 16-C). It is also available as a transdermal patch. 

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