Sympathetic nervous system agents

Signs and symptoms of sympathetic nervous system activity are invariably found in MH. Levels of catecholamines are markedly increased in MH. Whether activation of the sympathetic nervous system is a primary or a secondary response in the syndrome has not been fully elucidated. Gronert reported that stress-induced sympathetic hyperactivity can initiate a malignant hyperthermic episode in susceptible swine without a triggering agent. Stress-induced MH in humans has been inferred because susceptible families have been shown to have an increased incidence of sudden death. Gronert s reasons that activation of the sympathetic... 

Overactivation of the sympathetic nervous system (SNS) may also play a role in the development and maintenance of primary hypertension for some individuals. Among other effects, direct activation of the SNS may lead to enhanced sodium retention, insulin resistance, and baroreceptor dysfunction.9 Regardless of which mechanism(s) underlie the role the SNS may play in the development of primary hypertension, the SNS remains a target of many antihypertensive agents. 

The sympatholyfics of this type interfere with the /3i- and /S2-adrenoceptor subtypes. Via this mechanism the stimulating influence of the sympathetic nervous system on the heart and the metabolism and its inhibiting influence on smooth muscle is blocked. /3-Adrenoceptor blocking agents, or /3-blockers, mostly have a typical isoproterenol-like structure with an isopropylamine or a tertiary butylamine group and a substituted phenoxy moiety bound to the isopropanol backbone. The substituents determine the physicochemical properties of the particular drug and thereby its pharmacokinetic proflle. 

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

Patients with anxiety have a variety of psychic and somatic symptoms. The peripheral manifestations of anxiety may include a number of symptoms (e.g., palpitations) that are due in part to overactivity of the sympathetic nervous system. The 3-blocking agents may offer some benefit in the treatment of anxiety. 

A unique property of bretylium as an antiarrhythmic agent is its positive inotropic action. This effect, related to its actions on the sympathetic nervous system, includes an initial release of neuronal stores of norepinephrine followed shortly by a prolonged period of inhibition of direct or reflex-associated neuronal norepinephrine release. The onset of bretylium-induced hypotension is delayed 1 to 2 hours because the initial catecholamine release maintains arterial pressure before this time. 

The vasodilators decrease total peripheral resistance and thus correct the hemodynamic abnormality that is responsible for the elevated blood pressure in primary hypertension. In addition, because they act directly on vascular smooth muscle, the vasodilators are effective in lowering blood pressure, regardless of the etiology of the hypertension. Unlike many other antihypertensive agents, the vasodilators do not inhibit the activity of the sympathetic nervous system therefore, orthostatic hypotension and impotence are not problems. Additionally, most vasodilators relax arterial smooth muscle to a greater extent than venous smooth muscle, thereby further minimizing postural hypotension. 

Desflurane stimulates the sympathetic nervous system and causes abrupt transient tachycardia during induction or as the concentration of the agent is raised to meet the patient s changing needs. 

The chemical transmitters may be small molecules— notably acetylcholine, norepinephrine, epinephrine, serotonin, dopamine, or histamine. Acetylcholine and norpeinephrine are the dominant neurotransmitters in the parasympathetic and sympathetic nervous systems, respectively. Dopamine and serotonin are employed primarily in the central nervous system. Neurotransmitters may also be more complex peptides (small proteins) such as substance P, vasopressin, endorphins, and enkephalins. The latter agents are of particular importance to our considerations of opium since they represent the endogenous opiates—agents that exist within the body whose actions are mimicked by exogenous, or outside, agents such as morphine, heroin, codeine, and so on. These neurotransmitters serve to convey information between neurons across the synaptic cleft (the junction where two neurons meet) or at the neuroeffector junction (the site between neuron and an innervated organ such as muscle or secretory gland). 

Each neuron has specific synthetic machinery that enables it to both synthesize and eliminate a specific neurotransmitter. For example, neurons of the sympathetic nervous system employ norepinephrine and epinephrine as their transmitters. Other neurons, particularly in the central nervous system, employ dopamine as their transmitter. Dopamine is a particularly important transmitter for a variety of neuronal functions. Its loss is associated with Parkinson disease, and it is a critical agent in the mediation of pleasure and reward processes. Dopamine, due to its association with pleasurable sensations, is widely implicated in the actions of a number of drugs of abuse, including cocaine, opiates, and methamphetamines. 

Beta-blocking drugs (eg, propranolol) may be used as antianxiety agents in situations such as performance anxiety. The sympathetic nervous system overactivity associated with anxiety appears to be satisfactorily relieved by the fblockers, and a slight improvement in the nonsomatic components of anxiety may also occur. Adverse central nervous system effects of propranolol include lethargy, vivid dreams, and hallucinations. 

Angiotensin II is an octapeptide, which was initially described as a potent vasoconstrictor agent. However, its functions have since been expanded to include regulation of cell growth, inflammation, electrolyte and water balance, hormone secretion, sympathetic nervous system activity, differentiation, and apoptosis. The discovery that it is produced both systemically and locally was instrumental in establishing a pivotal role for the peptide in several disease states, including hypertension, coronary heart disease, myocarditis, congestive heart failure, atherosclerosis, and nephrosclerosis. 

---