Alcohol

1. Alcohol • Pharmacology • Acute and Chronic use and the effects on Anaesthesia • Alcohol withdrawal

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

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

6. Implications for anaesthesia?

8. 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, esophagealvarices, 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

9. 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.

10. 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

11. 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 NMDAglutamate 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.

12. 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?

13. Dexmedetomidine- The new magnesium? • 8 times more selective for the α2-receptor than clonidine • Produces sedation, anxiolysis, and sympatholysis through agonism of central presynapticα2-autoreceptors with no activity at GABA or opioidreceptors - sedation without respiratory compromise • Animal Studies: superior to propranolol in reducing withdrawal symptoms, strengthening the theory that dexmedetomidinemay 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

14. Problems The good news 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) • 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

15. 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”

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