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Alcohol-Pharmacology of Detox and Beyond D Raquin Cherian Specialty Registrar(ST4) MRCPsych Course Cambridge 16th October 2012 Aims of Teaching Pharmacological treatment in alcoholism and brief pathophysiology Different medications used in detox and indications Different treatment regimes used Medicines used to treat complications of detox Medicines that help maintain abstinence from alcohol and how do they differ Importance of Pharmacological Rx of withdrawal Withdrawal is a dangerous time for the brain Complications including delirium tremens, seizures, even death if untreated Appears to have long lasting consequences for those who go through even medicated detox. Adequate pharmacological treatment of alcohol withdrawal critical in preventing and treating complications during detox. Action of Alcohol in the Brain Inhibitory/Excitatory imbalance GABA Potentiates GABA (inhibitory) neurotransmitter at the GABA-A receptor (Explain why Alcohol is an effective anxiolytic!) Brain downregulates GABA receptors and change their response to GABA. In withdrawal, the brain is in a hypoGABAergic state, ( explains the profound anxiety and propensity for seizures during alcohol withdrawal ) When we treat alcohol withdrawal with benzodiazepines we are potentiating the action of GABA – although BDs attach to a different receptor site on the GABA chloride channel – the effect is similar. We use long-acting benzos with active metabolites so the decrease in GABA potentiation is gradual and the brain can adapt. driest martini! Inhibitory/Excitatory imbalance NMDA Alcohol antagonises NMDA transmission (glutamatergic) ie. Excitatory. Chronic alcohol intake: increase in NMDA receptors withdrawal: hyperglutamatergic state . NMDA transmission in excess is neurotoxic acting via Calcium. Acamprosate : neuroprotective by blocking some NMDA transmission and rise in glutamate during withdrawal. Similarly, anticonvulsants such as carbamazepine act via inhibiting calcium influx, thus mitigating excitatory excess. CBZ also binds to certain subtypes of the GABA-A receptor. Alcohol’s effects on endogenous opioids and the mesolimbic dopamine system Alcohol Withdrawal Symptoms of Alcohol Withdrawal Time of appearance after last drink Minor sx:insomnia,tremor,mild anxiety,GI sx;headache,perspiration and Palpitation 6-12 Hours Visual,auditory,Tactile hallucinations 12-24 hours(usually resolved within 48 hours) Withdrawal seizures 24-48 hours(Has been reported early as 2 hours) Delerium Tremens 48-72 hours(peaks at 5 days after cessation) Aims of Detox medications Manage withdrawal Relapse prevention and maintain abstinence Prevention of complication of withdrawal e.g WE Reduction of harm associated with alcohol use Indications for inpatient detox H/o severe withdrawal sx H/o seizures/DTs Concommitent serious medical/psychiatric conditions Multiple past detoxifications(kindling)) Recent high levels of alcohol consumption Lack of reliable social support Pregnancy Older adults Kindling Predictors of severe /complicated withdrawal Recent high amounts of alcohol consumption Hx of severe withdrawal Hx of seizures or DTs Concomitant use of other psychoactive drugs Poor physical health Coexisting psychiatric disorder elderly Detox Pharmacology Drugs that can correct the excitatory/inhibitory imbalance: Benzos, Carbamazepine etc Symptomatic treatment: Metochlopramide, Loperamide, Sedatives. Vitamin Supplements: Thiamine, Vitamin B co forte Correct electrolyte imbalance: Mg, PO4, K deficiency Treatment of complications Medicines used for detox Benzodiazepines Carbamazepine : equally efficacious but not commonly used in UK Clormethiazole reserved for inpatient settings Use only after due consideration of its safety Which Benzos and when Diazepam: Immediate onset and long acting-if risk of seizures high, co-morbid benzo dependence Oxazepam: Short acting and delayed onset of actionsevere liver damage Lorazepam: intermediate onset of action, short actingseizures and deranged LFT Chlordiazepoxide: intermediate onset of action and long acting, less abuse potential. All other detox scenarios Treatment Regimes Fixed Dose Regime (Refer to hand out) Routine use Used in community and inpatient setting Symptom triggered (Refer to hand out) Only with adequate monitoring (inpatient) Use a withdrawal rating scale e.g CIWA ar Front Loading with Diazepam Treatment of complications Seizures Benzodiazepines, particularly diazepam, prevent de novo seizures Lorazepam effective in preventing a second seizure in the same withdrawal episode Anticonvulsants : equally as efficacious but no advantage when combined Treatment of complications Delirium Benzodiazepines:Diazepam and Chlordiazepoxide(long half life) prevent Delerium and should be used to treat Haloperidol for hallucination Correct electrolyte imbalance Supportive management Treatment of complications WKS Thiamine replacement critical Parenteral Route for treatment of WE and those at risk a. > 15SAU/ day for a month or more b. recent weight loss or vomiting or diarrhoea c. malnutrition d. peripheral neuropathy e. chronic ill- health. Thiamine-Dose and Route Low risk of WE: Oral thiamine >300 mg/day ,during detoxification. Prevention of WE : 250 mg thiamine (one pair of ampoules Pabrinex®) i.m/ i.v. once daily for 3–5 days or until no further improvement is seen Treatment of WE : Thiamine >500 mg should be given i.m/i.v for 3–5 days (i.e. two pairs of ampoules Pabrinex® three times a day for 3-5 days), followed by one pair of ampoules once daily for a further 3–5 days depending on response Abstinence aiding medications- Acamprosate Glutamatergic NMDA antagonist (alcohol dependence and withdrawal are hyperglutamatergic )-potentially neuroprotective ?Anticraving. Anxiolytic ,insomnia Should be started during detoxification (BAP). prescribe 6months Moderately effective in increasing abstinence after detoxification Some evidence : also reduce ‘heavy drinking’ after relapse Well tolerated. Good safety profile even with physical comorbidity Use with caution / contraindicated in severe liver and renal impairment . Abstinence aiding medication: Naltrexone Non-selective opioid antagonist. Reduces alcohol’s rewarding effects and motivation to drink or ‘craving’ (mu opioid receptor-Dopaminergic activity) Impulse control: pathological gambling esp those with a family history of alcoholism. Comorbid cocaine/alcohol dependence reduced cocaine and alcohol use in men but not women. Start soon after detox. Prescribe for 6 months Not licensed in the UK but can be used and NICE recommended Acamprosate or Naltrexone No overall superiority of Naltrexone over Acamprosate that would apply to the UK patient population. (BAP) Acamprosate more effective in preventing a lapse Naltrexone prevents better at a lapse from becoming a relapse. Abstinence aiding medication Disulfiram(antabuse) blocks aldehyde dehydrogenase- accumulation of acetaldehyde if alcohol is consumed- nausea, flushing, and palpitations-deters people from drinking. “deterrent” blocks dopamine-b-hydroxylase - increase dopamine and reduce noradrenaline Cautiuos approach: alcohol-antabuse reaction, lasts upto 7 days after last dose. Pt should be warned. should be tried after acamprosate or naltrexone, or where the patient indicates a preference (NICE). Started after alcohol free for at least 24 hr. No guidance on max duration of prescribing Witnessing intake improves compliance - effectiveness Other Drugs Baclofen Topiramate Pregabalin SSRIs: In those without comorbid depression, their use cannot be recommended (BAP) Abstinence Medications Conclusions Relapse prevention medication to be considered for everyone who is alcohol dependent wanting to be abstinent . Acamprosate : improve abstinence rates . continued if the person starts drinking as it reduces alcohol consumption Naltrexone :prevents lapse becoming a relapse, better choice if someone is ‘sampling’ alcohol regularly but wishes to be abstinent. Disulfiram effective if intake is witnessed. treatment option for patients who intend to maintain abstinence, and for whom there are no contraindications . Baclofen :intents abstinence, has high levels of anxiety and not benefited from/ unable to take acamprosate, naltrexone or disulfiram . SSRIs should be avoided, or used with caution in type 2 alcoholism. Multiple choice questions:1 Where depression and anxiety are prominent predetoxification features, they: should be treated with standard pharmacotherapy should receive an ICD diagnosis immediately commonly disappear three weeks post-detoxification indicate the need for in-patient detoxification predict drop-out from detoxification. MCQ:2 The following items are part of the Windsor Clinic Alcohol Withdrawal Assessment Scale that predict serious withdrawal problems: quality of contact tremulousness thought disturbance seizures pulse rate. MCQ:3 Severe withdrawal is often associated with the following medical complications: Wernicke's encephalopathy magnesium deficiency hyperglycaemia hypotension polydrug use. MCQ:4 Preparation for detoxification should include: checking the patient is at the determination or action stage of change planning the post-detoxification week identifying a support person agreeing the detoxification regimen making an after-care appointment. MCQ:5 The following can be considered as suitable first-line drugs for detoxification: carbamazepine chlordiazepoxide clomethiazole chlorpromazine clonidine. What have we learnt? Importance of detox Brief pathophysiology of alcoholism Setting,regimes and medication used for detox Medicines used to support Relapse prevention Some useful resources: NICE guidelines;BAP Guidelines;management of Alcohol detoxification-APT 2000: Duncan Raistrick END