Alcohol Pharmacology Acute and Chronic use and the effects on Anaesthesia Alcohol withdrawal

http://www.edserv.musc.edu/clinpk/resources/zero_order/unit1.lasso

Consequences of high Acetaldehyde Poor mitochondrial function Results in less conversion to acetic acid – vicious cycle ? Role in addiction – altered neurotransmitters that resemble morphine

Oxidative phosphorylation ETC

Implications for anaesthesia?

Metabolic complications Alcoholic ketoacidosis (AKA) Electrolyte disorders (eg, hypomagnesemia, hypokalemia, hypernatremia) Vitamin deficiencies (eg, thiamine, phytonadione, cyanocobalamin, folic acid) GI complications Pancreatitis Gastrointestinal bleeding (eg, peptic ulcer, esophageal varices, gastritis) Hepatic cirrhosis Infectious complications Pneumonia Meningitis Cellulitis Neurologic complications Wernicke-Korsakoff syndrome (Confusion,ataxia,opthalmoplegia) Cerebral atrophy Cerebellar degeneration Subdural or epidural hemorrhage Peripheral neuropathy

Alcohol Withdrawal Mild withdrawal usually occurs within 24 hours of the last drink and is characterized by tremulousness (shakes), insomnia, anxiety, hyperreflexia, diaphoresis, mild autonomic hyperactivity, and GI upset. Moderate withdrawal usually occurs 24-36 hours after the cessation of alcohol intake and includes intense anxiety, tremors, insomnia, and excessive adrenergic symptoms. Severe withdrawal usually occurs more than 48 hours after a cessation or decrease in alcohol consumption. It is characterized by profound alteration of sensorium including disorientation, agitation, and hallucinations; along with severe autonomic hyperactivity including tremulousness, tachycardia, tachypnoea, hyperthermia, and diaphoresis.

Some ‘useful’ facts? 25% of patients with a prolonged history of alcohol abuse have alcoholic hallucinosis - not necessarily followed by DT 23-33% of patients with significant alcohol withdrawal have alcohol withdrawal seizures ("rum fits") - typically terminate spontaneously or are easily controlled with benzodiazepines Status epilepticus < 3% - Ix for other cause DT occurs 48-72 hours after the last drink. Includes all early and intermediate symptoms of alcohol withdrawal and a profoundly altered sensorium (disorientation, agitation, and hallucination). Severe autonomic derangements (including diaphoresis, tachycardia, tachypnea, and hyperthermia) are common DT may present without preceding seizures

Delirium Tremens altered mental status (global confusion) and sympathetic overdrive (autonomic hyperactivity) medical emergency with a high mortality rate Chronic Etoh - Increased release of endogenous opiates; activation of the GABA-A receptor and a decrease in GABA-A receptor function, with a resultant influx of Cl ions; Inhibition of the NMDA glutamate receptor (mediates the postsynaptic excitatory effects of glutamate) with up-regulation; and interactions with 5HT and DA receptors. Withdrawal from alcohol - loss of GABA-A receptor stimulation causes a reduction in chloride flux and is associated with tremors, diaphoresis, tachycardia, anxiety, and seizures; lack of inhibition of the NMDA receptors may lead to seizures and delirium. Excessive nervous system excitability during periods of abstinence from alcohol is related to the effect of alcohol on the number and function of brain receptors.

Pharmacological Rx ABC…DEFG…. Thiamine! Benzos (lorazepam, diazepam, oxazepam, chlodiazepoxide, midazolam) These drugs produce sedative effects by enhancing GABA neurotransmission from binding to GABAA receptors. All benzodiazepines appear similarly effective in the treatment of alcohol withdrawal syndrome. In moderate-to-severe withdrawal, long-acting agents are preferred over short-acting drugs. Symptom-triggered therapy is preferred over fixed-schedule therapy because it decreases the duration and total dose of treatment to resolve symptoms. Fixed-dose therapy is appropriate in mild-to-moderate withdrawal. Propofol (glutamate + GABA-A), barbiturate - refractory Haloperidol (QT and seizure threshold), carbamazepine, valproic acid, clonidine, and beta-blockers, MgSO4 - not as single agents gabapentin, pregabalin – awaiting more data Ethanol – inferior and not recommended Dexmedetomidine?

Dexmedetomidine- The new magnesium? 8 times more selective for the α2-receptor than clonidine Produces sedation, anxiolysis, and sympatholysis through agonism of central presynaptic α2-autoreceptors with no activity at GABA or opioid receptors - sedation without respiratory compromise Animal Studies: superior to propranolol in reducing withdrawal symptoms, strengthening the theory that dexmedetomidine may have a benefit in alcohol withdrawal outside of just decreasing elevated noradrenergic tone Case Studies: may allow for a reduction in benzodiazepine doses, as well as reduce the need for other adjunctive medications, such as anticonvulsants and antipsychotics

No registration or RCTs Problems The good news Initial loading dose - bradycardia and hypertension due to effect on peripheral α2b-receptors in vascular smooth muscle . Is a load necessary? No benefit in the prevention or treatment of alcohol withdrawal seizures or delirium tremens No registration or RCTs Adverse effect profile compares well with that of other options Midazolam: drug accumulation - difficult awakenings; Barbiturates: narrow therapeutic index and respiratory depression; Lorazepam infusions: propylene glycol toxicity and metabolic acidosis; Propofol: hypertriglyceridemia, pancreatitis, and propofol infusion syndrome Has been used without additive toxicity in combination with a variety of different medications (benzodiazepines, propofol, fentanyl, and morphine)

The Verdict? Role for α2-agonists is as adjunctive medication to benzodiazepines “Positive findings from case reports on use of dexmedetomidine, coupled with its ease of use, safety profile, and lack of intubation requirements, make this medication a valuable choice for alcohol withdrawal in the ICU”

Methanol/ethylene glycol HAGMA Osmolar Gap > 10 Measured osmolality - Calculated osmolality 2x Na + Glucose + Urea Treat with ethanol or dialysis