Quanil Mechanism of Action

Pharmacotherapeutic group: Psychostimulants and nootropic agent. ATC code: N06BX06.
Pharmacology: Pharmacodynamics: Citicoline stimulates the biosynthesis of structural neuronal membrane phospholipids, as demonstrated in studies with magnetic resonance spectroscopy. Citicoline by this action improves the function of the mechanisms of membrane, such as the operation of pumps and ion exchange receptors embedded in it, whose modulation is essential for proper neurotransmission. Citicoline by its membrane stabilizing action, has properties that favor reabsorption of cerebral edema.
Experimental studies have shown that citicoline inhibits the activation of specific phospholipases (A1, A2, C and D), reducing free radical formation, avoiding the destruction of membranous and preserving antioxidant defense systems, such as glutathione. Citicoline protects the reserve neuronal energy; it inhibits and stimulates the synthesis of acetylcholine. Experiments have shown that citicoline also has prophylactic neuro-protective effect in models of focal cerebral ischemia.
Clinical trials have shown that citicoline significantly improves the functional development in patients with acute ischemic stroke, coinciding with slower growth of cerebral ischemic injury in brain imaging tests. In patients with head injury, citicoline accelerates recovery in these patients and reduces the duration and intensity of post-concussion syndrome. Citicoline improves the level of attention and awareness, as well as acts favorably on amnesia and cognitive impairment and neurological disorder associated with cerebral ischemia.
Pharmacokinetics: Citicoline is a water-soluble compound with greater than 90 percent bioavailability. Pharmacokinetic studies on healthy adults show oral doses of citicoline are rapidly absorbed, with less than one percent excreted in feces. Plasma levels peak in a biphasic manner, at one hour after ingestion followed by a second larger peak at 24 hours post-dosing. Citicoline is metabolized in the gut wall and liver. The byproducts of exogenous citicoline formed by hydrolysis in the intestinal wall are choline and cytidine. Following absorption, choline and cytidine are dispersed throughout the body; enter systemic circulation for utilization in various biosynthetic pathways and cross the blood-brain barrier for resynthesis into citicoline in the brain.
Pharmacokinetic studies using ¹⁴C citicoline show citicoline elimination occurs in two phases mirroring the biphasic plasma peaks, mainly via respiratory CO₂, and urinary excretion. The initial peak in plasma concentration is followed by a sharp decline, which then slows over the next 4-10 hours. In the second phase, an initially rapid decline after the 24-hour plasma peak is similarly followed by a slower elimination rate. The elimination half-life is 56 hours for CO₂, and 71 hours for urinary excretion.
Endogenous citicoline serves as an intermediate in the biosynthesis of phospholipids, including phosphatidylcholine, the primary phospholipids in cell membranes. Cytidine, a major component of RNA, undergoes cytoplasmic conversion to cytidine triphosphate (CTP). In the citicoline metabolic pathway, choline is phosphorylated by the enzyme choline kinase; the resulting phosphorylcholine combines with CTP to form citicoline. Citicoline then combines with diacylglycerol (DAG), forming phosphatidylcholine, with choline phosphotransferase serving as the enzyme catalyst in this reaction.
Oral administration of citicoline raises plasma levels of cytidine and choline in rats within six to eight hours. Prolonged administration for 42 and 90 days increases brain concentrations of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine - the three major phospholipids in brain cell membranes. Evidence for the role of these metabolites as substrates for phosphatidylcholine synthesis was found in a study giving rats daily oral doses of citicoline for 90 days. At a dose of 500 mg/kg per day phosphatidylcholine levels increased by 25 percent, phosphatidylethanolamine by 17 percent, and phosphatidylserine by 42 percent. Administration of citicoline to aged rats activates CTP:phosphocholine cytidylyltransferase, the rate-limiting enzyme in the citicoline pathway of phosphatidylcholine synthesis in the brain cell membrane. Choline and cytidine are the major metabolites released via hydrolysis of citicoline during absorption.
A single oral dose of citicoline raises plasma choline levels in both younger and older subjects. Using protein magnetic resonance spectroscopy, it was found that brain choline levels in older subjects decreased after citicoline administration but increased in younger subjects. The postulated explanation is that the cytidine moiety of citicoline may be taken up by brain cells in older adults more rapidly than choline. Based on this finding, it is suggested that cytidine is the citicoline component primarily responsible for stimulating phosphatidylcholine synthesis in older subjects. Using protein-decoupled phosphorus magnetic resonance spectroscopy, it has been shown that citicoline administration to older subjects for six weeks increases brain levels of phosphodiesters, byproducts of phospholipids metabolism. This is seen as evidence that citicoline increases phospholipids synthesis and turnover, which may help reverse cognitive functional deficits associated with aging. In clinical trials, citicoline has been administered orally and by intramuscular injection.