Alpha-agonist

Mephenteramine [Wyamine). This alpha-1 stimulant is used primarily to maintain or restore blood pressure during hypotensive episodes that may occur during spinal anesthesia. It is typically administered by intravenous or intramuscular injection. 

Methoxamine [Vasoxyl). This drug is used primarily to increase and maintain blood pressure in severe, acute hypotension, especially during general anesthesia and spinal anesthesia. It is usually administered by injection (intramuscularly or intravenously) to allow a rapid onset. 

Midodrine (ProAmatine). Midodrine can be administered orally to treat resistant cases of orthostatic hypotension. This drug can also prevent hypotension in patients undergoing dialysis, and it can offset the hypotensive effects of certain psychotropic drugs (e.g., antipsychotic medications). 

Oxymetazoline (Afrin, Visine, many others). This drug is used in nose drops and nasal sprays to decrease nasal congestion through alpha- 1-mediated vasoconstriction. Higher or systemic doses may also cause hypotension, presumably because central nervous system (CNS) alpha-2 receptors are stimulated in a manner similar to clonidine (see Alpha-2-Selective Agonists ). Oxymetazoline can also be administered as eye drops to decrease redness and minor eye irritation. 

Phenylephrine (Neo-Synephrine, others). Like methoxamine, phenylephrine can be administered systemically to treat hypotension, and phenylephrine can also be used to terminate certain episodes of supraventricular tachycardia. In addition, phenylephrine is administered topically to treat nasal congestion and is found in many over-the-counter spray decongestants. 

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Masson, S., Masseroh, M., Fiordaliso, F., et al. (1999) Effects of a DA(2)/alpha(2) agonist and a beta(l)-blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodeling in an experimental model of left ventricular dysfunction after coronary artery occlusion. J. Cardiovasc. Pharmacol. 34, 321-326. 

Balldin, J., Berggren, U., Eriksson, E., Lindstedt, G., and Sundkler, A. (1993) Guanfacine as an alpha-2-agonist inducer of growth hormone secretion a comparison with clonidine. Psychoneuroendocrinology 18 45-55. 

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. 

Norepinephrine One theory about the biological basis of panic disorder is that there is an initial excess of norepinephrine (Fig. 9—3). This theory is supported by evidence that panic disorder patients are hypersensitive to alpha-2 antagonists and hyposensitive to alpha-2 agonists. Thus, yohimbine, an alpha-2 antagonist, acts as a promoter of norepinephrine release by cutting the brake cable of the presyn-aptic norepinephrine autoreceptor, as shown earlier in Figure 7—6. The consequence... 

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. 

Adverse Effects. The most common side effects associated with tizanidine include sedation, dizziness, and dry mouth.40 As indicated, however, tizanidine tends to have a more favorable side effect profile than other alpha-2 agonists, and this drug produces less generalized weakness than oral baclofen or diazepam. Tizanidine may therefore be a better alternative to these other agents in patients who need to reduce spasticity while maintaining adequate muscle strength for ambulation, transfers, and so forth. 

Alpha-2-selective drugs are used primarily in the treatment of hypertension and spasticity. When treating hypertension, these drugs stimulate alpha-2 receptors located in the brain and brainstem. When stimulated, these central alpha-2 receptors exert an inhibitory effect on sympathetic discharge from the vasomotor center in the brainstem.34 Diminished sympathetic discharge results in a decrease in blood pressure. The use of alpha-2 agonists in lowering blood pressure is discussed in more detail in Chapter 21. 

Alpha-2 receptors have also been identified on interneurons in the spinal cord. Stimulation of these receptors causes interneuron inhibition, and a subsequent decrease in excitability of motor neurons supplied by the interneurons.6,8 Alpha-2 agonists have therefore been used to normalize neuronal activity in conditions such as spasticity the use of these drugs as antispasticity agents is discussed in more detail in Chapter 13. 

Methyldopa (Aldomet). Methyldopa has been used as an antihypertensive drug for some time, but its mechanism of action is poorly understood. Currently, methyldopa is believed to exert its effects by being converted to alpha-methylnorepinephrine in the body.26 Alpha-methylnorepinephrine is a potent alpha-2 agonist that lowers blood pressure by stimulating inhibitory central adrenergic receptors in a manner similar to clonidine and guanabenz. 

Ossipov MH, Gebhart GF (1983) Absence of antinociceptive effect of alpha-2 agonists microin-jected in the periaqueductal gray of the rat. Brain Res 289 349-354 Ossipov MH, Kovelowski CJ, Wheeler-Aceto H, Cowan A, Hunter JC, Lai J, Malan TP, Porreca F (1996) Opioid antagonists and antisera to endogenous opioids increase the nociceptive response to formalin demonstration of an opioid kappa and delta inhibitory tone. J Phtirmacol Exp Ther 277 784-788... 

Guanfacine Is a related centrally active alpha 2 agonist hypotensive agent that has been used for similar CNS applications but has not been as widely Investigated or used as clonidine... 

Chacko DM, Camras CB.The potential of alpha-2 agonists in the medical treatment of glaucoma. Curr Opin Ophthalmol 1994 5 76-84. 

Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol 2003 1 S47-S51. 

Wheeler LA, Lai R, Woldemusie E. From the lab to the clinic activation of an alpha-2 agonist pathway is nenroprotective in models of retinal and optic nerve injnry. Eur J Ophthalmol 1999 9 S17-S21. 

Unnerstall JR, Kopajtic TA, Kuhar MJ. 1984. Distribution of alpha 2 agonist binding sites in the rat and human central nervous system Analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Res 319 69-101. 

Sympatholytic syndrome. Blood pressure and pulse rate are both decreased (peripheral alpha blockers may cause hypotension with reflex tachycardia). The pupils are small, often of pinpoint size. Peristalsis is often decreased. (Examples centrally acting alpha-2 agonists [clonidine and methyidopa], opiates, and phenothiazines.)... 

B. Guanabenz is structurally similar to guanethidine, a ganglionic blocker. Guanfacine is related closely to guanabenz and has more selective alpha-2-agonist activity than clonidine. 

Tizanidine, a centrally acting alpha-2 agonist, has effects similar to cloni-dine (see p 169)... 

Uncertain. A possible reason is that, like elonidine (another alpha-2 agonist), the uptake of guanfaeine into neurones within the brain is blocked by tricyclic antidepressants, thereby redueing its effeets. 

Alpha 2 agonists may have diminished antihypertensive effects. 

Tizanidine and clonidine are both alpha-2 agonists. As evidenced by their differing effects on blood pressure, the specific pharmacodynamic profiles of the two drugs differ somewhat. This may be due to variation in the agonist activity at the specific alpha-2 receptor subtypes A, B, and C [26,27]. 

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