Mr White is an 80-year-old gentleman who has been taking diazepam at a dose of 20 mg at night for the past 3 years. During a trip to France to meet his nephew, he forgets to take his medication.
Which of the following is NOT likely to be a seen if he experiences benzodiazepine withdrawal?
C. Sedative-hypnotic (includes benzodiazepines, barbiturates and newer ‘z’ hypnotics) withdrawal syndrome is a spectrum of signs and symptoms that occurs after stopping daily intake of a sedative-hypnotic. Common signs and symptoms include anxiety, tremors, nightmares, insomnia, anorexia, nausea, vomiting, postural hypotension, seizures, delirium, and hyperpyrexia. The withdrawal syndrome is similar for all sedative-hypnotics, but the severity and time course depend on the pharmacokinetics of the individual agent used, besides a number of other risk factors. With short-acting medication, withdrawal symptoms typically begin 12–24 hours after the last dose and peak in intensity between 24 and 72 hours after the last dose. If the patient has liver disease or is over the age of 65, symptoms may develop more slowly. With long-acting medication, the withdrawal syndrome usually begins 24 to 48 hours after the last dose and peaks on the fi fth to eighth day. During untreated sedative-hypnotic withdrawal, the EEG may show bursts of high-voltage, low-frequency activity. This may precede a clinical seizure occasionally.
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Polymorphisms of genes encoding which of the following enzymes/receptors confers protection from alcohol dependence in certain ethnic groups?
A. ADH (alcohol dehydrogenase) and ALDH (aldehyde dehydrogenase) are the major enzymes involved in the degradation of ethanol; ADH catabolizes alcohol to acetaldehyde, which ALDH breaks down to acetate and water. A number of studies have shown that allelic variants of ADH and ALDH are associated with the risk for developing alcohol dependence. There are many ALDH gene families distributed on several different chromosomes. Family 2 genes (ALDH 2) located on chromosome 12 have been studied the most regarding an association with alcohol dependence. This family of genes encodes mitochondrial enzymes that oxidize acetaldehyde. ALDH 2 has an allelic variant called ALDH 2*2. This ALDH 2*2 variant is found in approximately 50% of the Asian population. Individuals with the ALDH 2*2 variant typically experience a disulfiram-like reaction when they take alcohol. This is sometimes called the ‘Asian flush’ or the ‘Oriental flush syndrome’. Several studies demonstrate the protective effect of ALDH 2*2 gene carriers from developing alcohol dependence. The other genes ALDH1, 3, 4 and 5 are responsible for the metabolism of other aldehydes in the body. Similarly a variant allele of the ADH gene (situated on chromosome 4) ADH 2*2 also confers protection to alcoholism, although this relationship is less robust than ALDH2*2.
Which of the following statements regarding alcohol use and comorbid depression is correct?
C. About 30–40% of people with an alcohol-related disorder meet the diagnostic criteria for a major depressive disorder sometime during their lifetime. It is more common in women. It is dose dependent, i.e. it is likely to occur in patients who have a high daily consumption of alcohol. It is also more common in those with a family history of alcohol abuse. Patients with depression and comorbid alcohol use disorders are at a greater risk for attempting/completing suicide and are likely to have other substance-related disorder diagnoses. Most estimates of the prevalence of suicide among people with alcohol-related disorders range from 10–15%, although alcohol use itself may be involved in a much higher percentage of suicides. Twenty to 50 percent of all people with alcohol-related disorders also meet the diagnostic criteria for an anxiety disorder. Phobias and panic disorder are particularly frequent comorbid diagnoses in patients with alcohol use disorders.
Which of the following best describes the mechanism of action of Acamprosate?
E. Acamprosate’s principal neurochemical effects have been attributed to antagonism of NMDA glutamate receptors, which restores the balance between excitatory and inhibitory neurotransmission that is dysregulated following chronic alcohol consumption. Recently, however, further mechanisms have been demonstrated. Thus acamprosate is said to have four principal effects: A) reducing post-synaptic excitatory amino acid neurotransmission at N-methyl-Daspartate (NMDA); B) diminishing Ca2+ influx into the cell, which interferes with expression of the immediate early gene c-fos; C) decreasing the sensitivity of voltage-gated calcium channels, and D) modulating metabotropic-5 glutamate receptors (mGluR5). The most common side effects are headache, diarrhoea, flatulence, abdominal pain, paraesthesias, and various skin reactions. Acamprosate is not metabolised by liver and is excreted unchanged by the kidney. Administration of disulfiram or diazepam does not affect the pharmacokinetics of acamprosate. Coadministration of naltrexone with acamprosate produces an increase in concentrations of acamprosate. Effect of acamprosate is dose dependent and has been confirmed by at least two studies in humans.
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Sam has been diagnosed with alcohol dependence. He has been started on disulfiram following a planned detoxification. You educate him about the effects and side-effects of the medication. Unfortunately, Sam decides to start drinking again after taking disulfiram for 3 weeks.
How long should he wait after stopping disulfiram before he can be sure of having no unpleasant side-effects?
D. Disulfiram inhibits aldehyde dehydrogenase producing a marked increase in blood acetaldehyde concentration if alcohol is consumed. The accumulation of acetaldehyde produces a wide array of unpleasant reactions, called the disulfiram–ethanol reaction, characterized by nausea, throbbing headache, vomiting, hypertension, flushing, sweating, thirst, dyspnoea, tachycardia, chest pain, vertigo, and blurred vision. The reaction occurs almost immediately after the ingestion of one alcoholic drink and can last from 30 minutes to 2 hours. A person taking disulfiram must be instructed that the ingestion/use of any quantity of alcohol (including alcohol-containing preparations of medicines, food, and cosmetics) would lead to the unpleasant reaction with dangerous consequences at times. Disulfiram should not be administered until the person has abstained from alcohol for at least 12 hours. This reaction can occur as long as 1–2 weeks after the last dose of disulfiram.
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