**3. Pathophysiology**

Ethanol (C2H5OH) is a two-carbon molecule with an attached hydroxyl group. Various alcoholic beverages contain between 5 and 40% of ethanol by concentration; one standard drink in the United States is defined as 14 grams of ethanol [3]. The molecule is slightly lipophilic and can penetrate the blood brain barrier as a result. The Central Nervous System (CNS) functions via a delicate balancing act between inhibitory γ-aminobutyric acid (GABA) receptors and excitatory glutamic N-methyl-D-aspartate (NMDA) receptors. Ethanol acts as a CNS depressant by primarily augmenting GABA receptors and antagonizing excitatory NMDA receptors [4]. At low CNS concentrations ethanol induces behavioral excitation and euphoria, whereas at higher concentrations, ataxia, drowsiness, and slurred speech are common. Longstanding alcohol consumption causes physical tolerance (increasing doses to achieve the same effect) in a multitude of CNS receptor sites, including NMDA, GABA, serotonin (5HT), glycine, G-protein coupled rectifying potassium channels, as well as several others [5]. Ethanol also directly binds to glutamate, thereby enhancing its inhibitory effect on the brain [6]. Several studies have demonstrated that specifically the δ-GABAA receptors appear to be most sensitive to ethanol [5]. These are most highly concentrated in the cerebellum, cortex, thalamic nuclei and brain stem, which correlates with the clinical manifestations of ethanol intoxication. Prolonged ethanol exposure also results in specific adaptive changes to GABA receptor concentration and subunit composition. As an example, decreased α1 and γ2 GABA subunit expression,

#### *Improving the Safety of Admitted Patients with Alcohol Use Disorder and Withdrawal DOI: http://dx.doi.org/10.5772/intechopen.110030*

as seen in those with AUD, is theorized to directly affect CNS inhibitory tone [5]. Additionally, there is an upregulation of excitatory NMDA receptors. As a result, chronically consuming ethanol can predispose individuals to a baseline excitatory state [5]. Ultimately this disruption of homeostasis serves as the basis for AWS.

When a chronic ethanol stimulus is abruptly discontinued, the underlying molecular changes yield AWS. CNS excitatory activity becomes relatively unopposed. Dysautonomia results from an enhanced sympathetic nervous system activity and manifests as tachycardia, hypertension, hyperthermia, tremor, nausea, and vomiting [7]. Alcohol withdrawal related seizures are theorized to originate primarily from excitatory activity in the brainstem (specifically the inferior colliculus), although evidence also supports involvement of the hippocampus [5]. Additionally, repeated episodes of withdrawal may result in permanent epileptic changes in the brain, thus lowering the seizure threshold and putting individuals at even higher risk of AWS induced seizures [5]. Dopamine signaling, another neurotransmitter implicated in AWS, is increased as well, and appears to be responsible for the symptoms of alcoholic hallucinosis [6]. "Kindling" is another phenomenon associated with AWS, where neurons becoming increasingly sensitive, and as a result, subsequent episodes of AWS can be more severe [5, 7]. Outside of its CNS manifestations, AWS and alcohol use disorder more broadly is also associated with varying degrees of electrolyte abnormalities, metabolic derangements, nutritional deficiencies, coagulopathies and many other co-morbidities due to the toxic effects of longstanding ethanol ingestion as will be detailed in subsequent sections.

In summary, neuro-adaptive changes resulting from longstanding, regular ethanol use predispose to an excitatory neurological state, that cascades through the spectrum of AWS following cessation of ethanol. As a result, patients suffer from a range of neurologic symptoms, some of which can be life threatening. It is critical that clinicians are familiar with these manifestations and can diagnose and treat them rapidly.
