Autonomic human functions

Effects of autonomic blockade on the response to phenylephrine (Phe) in a human subject. Left The cardiovascular effect of the selective K-agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal. In the absence of baroreflex buffering, approximately a tenfold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. 

Acetylcholine (Ach) is an ester of acetic acid and choline with the chemical formula CH3COOCH2CH2N+ (CH3)3. ACh functions as a chemical transmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in a wide range of organisms, humans included. Neurotransmitter involved in behavioral state control, postural tone, cognition and memory, and autonomous parasympathetic (and preganglionic sympathetic) nervous system. 

Fleishman JA, Hellinger FH (2003) Recent trends in HIV-related inpatient admissions 1996-2000 a 7-state study. J Acquir Immune Defic Syndr 34(1) 102-110 Freeman R, Roberts MS et al (1990) Autonomic function and human immunodeficiency virus infection. Neurology 40(4) 575-580... 

Monti-Bloch L., Diaz-Sanchez V. and Jennings-White C. (1998). Modulation of serum testosterone and autonomic function through stimulation of the male human vomeronasal organ with pregna-4, 20-diene-3,6-dione. J Steroid Biochem Molec Biol 65, 237-242. 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

Bensafi, M., Brown, W. M., Khan, R., Levenson, B. and Sobel, N. (2004) Sniffing human sex-steroid derived compounds modulates mood, memory and autonomic nervous system function in specific behavioral contexts. Behav. Brain Res. 152, 11-22. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

Green M, Loewenstein PM. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 1988 53(6) 921-926. 

O.E. Brodde, K. Leineweber, Autonomic receptor systems in the failing and aging human heart Similarities and differences, Eur. J. Pharmacol. 500 (2004) 167-176. O.E. Brodde, 1- and /t2-adrenoceptors in the human heart Properties, function, and alterations in chronic heart failure, Pharmacol. Rev. 43 (1991) 203-242. 

CFS patients and is related to autonomic dysfunction. In a separate rat study, Giannesini et al. used citrulline malate (CM) to treat asthenia and found that the supplementation prevented the basal PCr/ATP ratio reduction and normalized the pHi time-course during muscular activ-ity. They conclude that CM supplementation corrects the impaired control of oxidative function and has protective effect on basal energy metabolism. The data from either human or animal studies provide a potential approach to therapy. 

The human nervous system can be divided into two major functional areas the somatic nervous system and the autonomic nervous system (ANS). The somatic division is concerned primarily with voluntary function—that is, control of the skeletal musculature. The ANS is responsible for controlling bodily functions that are largely involuntary, or automatic, in nature. For instance, the control of blood pressure (BP) and other aspects of cardiovascular function is under the influence of the ANS. Other involuntary, or vegetative, functions such as digestion, elimination, and thermoregulation are also controlled by this system. 

Yohimbine, an indole alkaloid, is an -selective antagonist. It has no established clinical role. Theoretically, it could be useful in autonomic insufficiency by promoting neurotransmitter release through blockade of presynaptic 02 receptors. It has been suggested that yohimbine improves male sexual function however, evidence for this effect in humans is limited. Yohimbine can abruptly reverse the antihypertensive effects of an 2-adrenoceptor agonist such as clonidine—a potentially serious adverse drug interaction. 

The NE system mediates various autonomic, neuroendocrine, emotional and cognitive functions. One of the central roles of NE is response to stress and aversion. This role can be summarized as an activation of response to the acute stress and aversion, followed by decreased reaction to repeated or chronic aversion. Since the response to stress and aversion is a basic part in pathology of mood disorder, NE should play an important role in anxiety, depression and mania. Indeed, this role has been demonstrated in numerous animal and human studies. Majority of antidepressant drugs and mood stabilizers affect NE system as their direct or indirect target. Various medications have different effects on NE neuronal activity. The majority of antidepressants, Li and benzodiazepines suppress NE transmission. Other medications, such as AADs, activate NE neuronal firing activity and NE release. Appropriate combination of different medications, based on the consideration of their effect on NE system, might be critical to obtain good treatment outcome. The combination of SSRIs... 

Zonneveld, A-J. von, Veerman, H., and Pannekoek, H. (1986). Autonomous functions of structural domains of human tissue-type plasminogen activator. Proc. Natl. Acad. Sci. USA 83,4670 4674. 

---