The Royal Navy enlisted 184,899 sailors during the Seven Years War; 133,708 of these were "missing" or died from disease, and scurvy was the leading cause.Although throughout this period sailors and naval surgeons were increasingly convinced that citrus fruits could cure scurvy, the classically trained physicians who determined medical policy dismissed this evidence as merely anecdotal, as it did not conform to their theories of disease. Literature championing the cause of citrus juice, therefore, had no practical impact. The medical theory was based on the assumption that scurvy was a disease of internal putrefaction brought on by faulty digestion caused by the hardships of life at sea and the naval diet. Although this basic idea was given different emphases by successive theorists, the remedies they advocated (and which the navy accepted) amounted to little more than the consumption of fizzy drinks to activate the digestive system, the most extreme of which was the regular consumption of elixir of vitriol – sulphuric acid taken with spirits and barley water, and laced with spices. In 1764, a new and similarly inaccurate theory on scurvy appeared. Advocated by Dr David MacBride and Sir John Pringle, Surgeon General of the Army and later President of the Royal Society, this idea was that scurvy was the result of a lack of fixed air in the tissues which could be prevented by drinking infusions of malt and wort whose fermentation within the body would stimulate digestion and restore the missing gases.
Similar concern is appropriate when it is used with sedating medications.Guanfacine is known to lower the users tolerance for alcohol, heightening its effect, and alcohol use may prolong the effects of the medication. Pharmacology
Guanfacine is a highly selective agonist of the α2A adrenergic receptor, with low affinity for other receptors. However it may also be a potent 5-HT2B receptor agonist, which can be associated with valvulopathy, although not all 5-HT2B agonists have this effect. Mechanism of action
Guanfacine works by activating α2A adrenoceptors within the central nervous system. This leads to reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone, which lowers both systolic and diastolic blood pressure.In ADHD, guanfacine works by strengthening regulation of attention and behavior by the prefrontal cortex. These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A adrenoceptors on dendritic spines. cAMP-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing. The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University. Pharmacokinetics
Guanfacine has an oral bioavailability of 80%. There is no clear evidence of any first-pass metabolism. Elimination half-life is 17 hours with the major elimination route being renal. The principal metabolite is the 3-hydroxy-derivative, with evidence of moderate biotransformation, and the key intermediate is an epoxide. Elimination is not impacted with impaired renal function.