Alcohol Withdrawal. Introduction. Blood Alcohol Concentration. DSM-IV Criteria/Alcohol Abuse. Pharmacologic Effects of Alcohol

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1 Pharmacologic Effects of Alcohol Alcohol Withdrawal Kristi Theobald, Pharm.D., BCPS Therapeutics III Fall 2003 Inhibits glutamate receptor function (NMDA receptor) Inhibits excitatory neurotransmission Intoxication, impaired cognition and learning and blackouts Interaction with dopamine/serotonin receptors Increased levels of dopamine May be involved in the rewarding and reinforcing effects of alcohol Introduction DSM-IV Criteria/Alcohol Abuse Alcohol is the 2 nd most commonly abused drug in the U.S. Claims 100,000 lives annually ~400,000 persons are in alcohol treatment programs at any one time One or more of the following within a 12 month period Failure to fulfill major role obligations Exposure to physical hazards Legal problems Social or interpersonal problems Pharmacologic Effects of Alcohol Blood Alcohol Concentration Increase in endogenous opioids Activation of GABA-A-type receptormediated inhibitory chloride influx Potentiates inhibitory neurotransmission Anxiolytic and sedative effects Impaired motor function Review table in handout KEY POINT Laboratories report in mg/dl To convert to a percent, divide by 1000

2 Alcohol Withdrawal In patients who do not receive drug therapy for alcohol withdrawal, 15% develop seizures and 15% develop DTs. Development of alcohol withdrawal is dose dependent Clinical Presentation Delirium tremens Occurs hours after last drink Disorientation, confusion, hallucinations, diaphoresis, tachycardia, tremors, agitation, fever, incontinence Alcohol Consumption DSM-IV Criteria/Alcohol Withdrawal Increased endogenous opioids Reinforces consumption Development of tolerance Activation of inhibitory GABA receptors Down-regulation of GABA receptors Inhibition of excitatory NMDA glutamate receptors Up-regulation of glutamate receptors Withdrawal Minimal inhibition Excitotoxicity Chronic Abuse Cessation History of cessation/reduction in heavy/prolonged alcohol use 2 or more of the following symptoms: Autonomic hyperactivity Hand tremor Insomnia N/V Psychomotor agitation Hallucinations Anxiety Tonic-clonic seizures Clinical Presentation CIWA-Ar Scale Time since last drink important Signs/symptoms can begin within 6 hours of last drink but usually peak between 12 and 36 hours after last drink Tremors, anxiety, hyperreflexia, HTN, tachycardia, diaphoresis, N/V, insomnia, vivid dreams, hallucinations, seizures Clinical Institute Withdrawal Assessment Scale for Alcohol, revised Score Interpretation <8 Minimal to mild alcohol w/d, no drug therapy 8-14 Moderate alcohol w/d, consider drug therapy >15 Severe alcohol w/d, drug therapy indicated

3 Risk Factors Concomitant medical or surgical illness Moderate to severe w/d symptoms at baseline Older age Prior DTs/seizures Prior detoxification Time since last drink Severity of alcohol dependence Fixed schedule Chlordiazepoxide mg q 6h x 1 day followed by 25-50mg q 6h x 2 days Lorazepam 2mg q 6h x 1 day followed by 1mg q 6h x 2 days Front-loading Diazepam 20mg q 2h until symptoms resolve Pharmacologic Therapy Patients who should definitely receive drug therapy CIWA-Ar score > 15 CIWA-Ar score 8-14 with risk factors History of alcohol w/d seizures Symptom-triggered Delivers medication only when the patient is symptomatic (CIWA-Ar > 8) Chlordiazepoxide mg q 1h prn Lorazepam 2mg q 1h prn Drugs of choice MOA Facilitate the inhibitory effect of GABA on neuronal excitability by increasing membrane permeability to chloride ions Treatment regimens Fixed schedule Front-loading Symptom-triggered Choosing appropriate regimen Fixed schedule if h/o DTs, w/d seizures or other risk factors for severe alcohol w/d Symptom-triggered therapy As effective as fixed schedule Usually less drug needed More rapid detoxification Requires use of CIWA-Ar scale which involves close monitoring and trained staff

4 Monitoring Barbiturates Q1h until symptoms controlled then q4-8h Electrolytes 2 nd most common drug class used Higher risk of a/e Respiratory depression Choice of Benzodiazepine Sympatholytics Age Severity of w/d symptoms Drug onset of action Drug duration of action IV vs. PO Cost LIVER FUNCTION Beta-blockers Clonidine Either can be used in combination with benzos when additional control of autonomic s/s is necessary Does not reduce DTs or seizures Choice of Benzodiazepine Anti-epileptics LIVER FUNCTION Metabolism/excretion Most benzos undergo hepatic oxidation followed by glucuronide conjugation and renal excretion Oxidation impaired in elderly and patients with liver disease Lorazepam and oxazepam conjugated only Lorazepam and oxazepam not coverted to desmethyldiazepam Carbamazepine Equal in efficacy to oxazepam for mild to moderate w/d s/s No serious adverse effects when used for only 7 days May prevent the kindling effect No potential for abuse Valproic acid Minimal clincal data to support use

5 Neuroleptics Alcohol Withdrawal Seizures Haloperidol 1-2mg IM/IV/PO q 6h prn Give in combination with benzos for marked agitation or hallucinations Treatment Diazepam 10mg IV x 1, then 5mg q 5min until calm but awake Carbamazepine and phenobarbital probably work Alcohol Delirium Tremens Not recommended Reinforces consumption Toxic effects Occurs in ~ 5% of patients who undergo alcohol w/d Typically begin hours after the last drink and last 1-5 days Mortality rate of 5% Treatment Diazepam 10mg IV x 1, then 5mg q 5min until calm but awake May require continuous infusion Alcohol Withdrawal Seizures Wernicke-Korsakoff Occurs in ~ 3% of chronic alcoholics Usually occur within 48 hours after last drink Usually single or recur only once or twice and resolve spontaneously Phenytoin will NOT prevent or treat alcohol w/d seizures Wernicke s encephalopathy Classic triad Encephalopathy Oculomotor dysfunction Gait ataxia Korsakoff s syndrome Retrograde and anterograde amnesia Confabulation

6 Wernicke-Korsakoff Pathophysiology Involves thiamine deficiency Treatment and prevention Thiamine 100mg IV x 1, then 100mg po qd Give before glucose Thiamine a cofactor in glucose metabolism Deficiency can be precipiated by a large glucose load