ALCOHOL DYNAMICS AND ABUSE

BY

DR. SYED SALEEM AHMED

PROFESSOR OF PHARMACOLOGY AND

CLINICAL THERAPEUTICS

ALCOHOL ABUSE AND DEPENDENCE• A primary chronic disease with genetic psychosocial and environmental factors: (1) Often progressive and fatal & characterized by impaired control over drinking (2)Preoccupation with the alcohol (3) Use of alcohol despite future consequences and (4)Distortions of thinking most notably denial.• Population-based epidemiologic studies have shown that alcohol use disorders are among the most prevalent medical behavioral or psychiatric disorders in the general population. • The prevalence in alcohol abuse and dependence in general outpatient and inpatient medical settings has been estimated between 15 and 40%.

PHARMAOKINETICS AND ALCOHOLISM• Women have lower levels of gastric alcohol dehydrogenase (enzyme responsible for metabolizing alcohol), they experience higher blood alcohol concentrations than men. • The absorption of alcohol can be affected by other factors, including the presence of food in the stomach and the rate of alcohol consumption.• By means of metabolism in the liver, alcohol is converted to acetaldehyde and acetate . • Metabolism is proportional to body weight• A genetic variation in a significant proportion of the Asian population alters the structure of an aldehyde hydrogenase isoenzyme, resulting in aldehyde syndrome

ALCOHOL WITHDRAWAL• The clinical manifestations of alcohol withdrawal include hyperactivity resulting in tachycardia and diaphoresis.• Patients also experience tremulousness, anxiety, and insomnia. More severe alcohol withdrawal can result in nausea and vomiting, which can exacerbate metabolic disturbances.• Perceptual abnormalities, including visual and auditory hallucinations and psychomotor agitation, are common manifestations of more moderate-to-severe alcohol withdrawal. • Grand mal seizures commonly occur during alcohol withdrawal, although they do not generally require treatment beyond the acute withdrawal phase.

ALCHOL WITHDRAWAL SYDROME• Tremor is typically among the earliest symptoms and can occur witahin 8 hours of the last drink. Symptoms of tremulousness and motor hyperactivity peak within 24 to 48 hours. Although mild tremor involves the hands, more severe tremors can involve the entire body and greatly impair a variety of basic motor functions. • Perceptual abnormalities begin within 24 to 36 hours after the last drink and resolve within a few days.• The withdrawal seizures are generalized tonic-clonic and most often occur within 12 to 24 hours after reduction of alcohol intake. •The most severe manifestations of the alcohol withdrawal syndrome are delirium tremens. This symptom complex includes disorientation, confusion, hallucination, diaphoresis, fever, and tachycardia. Delirium tremens begin after 2 to 4 days of abstinence, and the most severe form can result in death.

MAIFESTATION OF ALCOHOLISM• Acute manifestations, including intoxication and withdrawal, are generally stereotypical in their appearance and time course, • Chronic manifestations tend to be more varied. Many patients with alcohol dependence may be without evidence of any chronic medical manifestations for many years. • As time goes on, however, the likelihood that one or more of these manifestations will occur increases considerably.• The primary organ systems involved include the nervous system, cardiovascular system, liver, gastrointestinal system, pancreas, hematopoietic system, and endocrine system. • Patients may have the risk of a variety of malignancies, such as head and neck, esophageal, and liver cancers.• Excessive alcohol use often causes significant psychiatric and social morbidity.

ADVERSE EFFECTS OF ALCOHOL(1) In the CNS, the major effect is cognitive impairment.

Patients may present with mild-to-moderate short-term or long-term memory problems or may have severe dementia resembling Alzheimer’s disease . • The deficiency of vitamins such as thiamine may have a major impact in terms of promoting alcoholic dementia and severe cognitive dysfunction, as is seen in Korsakoff’s syndrome.• Alcohol also causes a polyneuropathy that can present with paresthesias, numbness, weakness, and chronic pain.• As with the CNS, peripheral nervous system effects are thought to be caused by a combination of the direct toxicity of alcohol and nutritional deficiencies.• A small proportion (<1%) of patients with alcohol dependence may develop midline cerebellar degeneration, which presents as an unsteady gait.

(2) CARDIOVASCULAR SYSTEM • The most common cardiovascular complications of chronic alcohol consumption are cardiomyopathy, hypertension, and supraventricular arrhythmias. • Alcoholic cardiomyopathy can present clinically in a manner similar to other causes of heart failure. It is the most common cause of non-ischemic cardiomyopathy in Western countries (44%). • Alcoholic cardiomyopathy also responds to conventional treatments for heart failure. Abstinence from alcohol can result in significant improvement.• Increasing levels of alcohol consumption also are associated with systolic and diastolic hypertension .• The most common arrhythmias associated with chronic alcohol use include atrial fibrillation and supraventricular tachycardia with acute intoxication and withdrawal.• Alcoholic cardiomyopathy also is associated with arrhythmias, in particular, ventricular arrhythmias.

(3) LIVER • Alcohol abuse is the major cause of morbidity and mortality from liver disease. • Factors that predispose to early liver disease include the quantity and duration of alcohol exposure, female gender, and malnutrition. • The clinical manifestations includes acute fatty liver, alcoholic hepatitis, and cirrhosis.• Fatty liver can be asymptomatic or associated with nonspecific abdominal discomfort ad generally improves with abstinence from alcohol. Alcoholic hepatitis can present as an asymptomatic condition identified through abnormalities in liver enzymes or as an acute episode with abdominal pain, nausea, vomiting, and fever. • Patients with alcoholic hepatitis have high levels of aspartate aminotransferase in the blood and elevated levels of γ-glutamyltransferase. The hepatitis improves with abstinence from alcohol.

(4) HEPATIC CIRRHOSIS• It is a major cause of death in the United States. • Although patients are often asymptomatic, patients with more advanced cirrhosis may present with a variety of symptoms and signs, including jaundice, ascites, and coagulopathy. • Cirrhosis is also associated with gastrointestinal bleeding from esophageal varices. • Although there is some controversy about the use of liver transplantation to treat patients with alcoholic cirrhosis, physicians believe that patients in established recovery are good candidates for liver transplantation in case of advanced cirrhosis.

(5) GASTROINTESTINAL DISEASE. • Chronic alcohol use is associated with a variety of esophageal problems, including esophageal varices, Mallory-Weiss tears, and squamous cell carcinoma of the esophagus.• The risk of squamous cell carcinoma is increased further in patients who smoke tobacco and drink alcohol. • Acute alcoholic gastritis presents with abdominal discomfort, nausea, and vomiting.

(6) PANCREAS• The risk of pancreatitis in individuals with alcohol dependence is approximately four times that in the general population. • It may present with severe abdominal pain, nausea, vomiting, fever, and hypotension and can be life-threatening.• Individuals with recurrent acute pancreatitis may develop chronic pancreatitis, which presents with chronic abdominal pain, malabsorption, weight loss, and malnutrition.

(7)HEMATOPOIETIC SYSTEM • The anemia can be multifactorial (e.g., blood loss, nutrient deficiency, secondary to liver disease and hyper-splenism). • The prevalence of anemia ranges from approximately 10 to 60%. Gastrointestinal blood loss owing to Mallory-Weiss tears , alcoholic gastritis or bleedig esophageal varices. • Dietary folate deficiency causes megaloblastic anemias . • Alcohol also has a direct toxic effect on the bone marrow, which can lead to sideroblastic anemia that resolves after abstinence .• Alcohol can suppress megakaryocyte production and causes thrombocytopenia manifesting as petechiae or bleeding .The platelet counts usually returning to normal after cessation of alcohol intake. • Alcohol-related immune dysfunction, as evidenced by decreased production and function of white blood cells and derangement in humoral and cell-mediated immunity causes higher risk for infectious diseases, such as pneumonia and tuberculosis. • The hypersplenism with cirrhosis contributes to the increased risk of serious infection seen in these patients

(8) MALIGNANCIES. • Alcohol intake has been associated with upper digestive, respiratory, and liver malignancies. • Alcohol use is associated with squamous cell carcinomas of the esophagus and of the head and neck. • Either heavy alcohol use or smoking individually increases the rate of oropharyngeal cancer by about 6 to 7 times that of the general population, whereas the risk for people with both risk factors is about 40 times. • Patients with alcohol-induced liver disease with a history of hepatitis B/C are at increased risk for hepatocellular carcinoma • Chronic alcohol use also associated with malignancies of the breast , prostate , pancreas, cervix, lung and colon. Hormonal mechanisms and direct carcinogenic effects of alcohol have been postulated as causes of this association. • The cervical cancer with alcohol dependence may be due to alcohol-associated with high-risk sexual behaviors .

(9)OTHER MEDICAL ISSUES. • Gout has been associated with alcohol abuse, and flares can occur at lower serum urate levels than in nonalcoholic patients .• Alcoholic ketoacidosis which usually follows an alcoholic binge, presents as nausea, vomiting, abdominal pain, volume depletion. • Mild or nonspecific• Abnormalities in thyroid function, may reflect abnormalities in the clearance of TSH oor elevated circulating estrogens . • Infertility and menstrual irregularities may occur presumably owing to alcoholic induced disruption in hypothalamic-pituitary dysfunction, gonadal toxicity, and impaired hepatic metabolism of circulating hormones. • Hypogonadism is highly prevalent in male alcoholics with cirrhosis • Alcohol dependence also is associated with dental and periodontal disease • Variety of dermatologic problems, including spider angiomas and,• Patients with poor hygiene and skin infestations.

(11) PSYCHIATRIC ISSUES• The prevalence of anxiety disorders is about 40%, and of affective disorders is about 30%. • Antisocial personality disorder is also more common. These psychiatric problems are more prevalent during periods of heavy drinking and withdrawal. • All patients with alcohol use disorders require careful screening for psychiatric illnesses. Effective treatment of underlying psychiatric disorders may result in improved drinking behaviors.

(12) OTHER BEHAVIORAL AND PSYCHOSOCIAL ISSUES• There may domestic injuries, trauma, motor vehicle accidents, and burns . Tobacco and other drug abuse are more prevalent in people with alcohol problems than in the general population.

Both acute and chronic alcohol use can lead to impotence in men. Increased blood alcohol concentrations lead to decreased sexual arousal, increased ejaculatory latency, and decreased orgasmic pleasure

USE OF STANDARDIZED SCREENING INSTRUMENTS

• Many standardized questionnaires have been developed to detect alcohol abuse and dependence. • The two questionnaires that have been evaluated most extensively in medical settings are the CAGE (Cut down, Annoyed, Guilty, and Eye opener) questionnaire and the Alcohol Use Disorder Identification Test (AUDIT). • The CAGE questionnaire includes four questions and is scored by giving 1 point for each positive response. Given that the word ever is used in each CAGE question, by definition this instrument is designed to detect lifetime alcohol problems and does not distinguish between lifetime problems and current problems. • To screen for alcohol abuse and dependence, the CAGE has a sensitivity of 43 to 94% and a specificity of 70 to 97% when a cutoff score of 2 is used to indicate a “positive” result.

BENZODIAZEPINES IN ALCOHOL WITHDRAWAL(1) The specific benzodiazepine and dose often depend

on: (i) Severity of withdrawal: (higher doses used if more severe) (ii) Presence of liver disease (Patients with severe liver disease should receive lower doses or shorter acting medications be used) (iii)Response to prior doses of medication. *The amount of medication per dosing period is decreased gradually as the withdrawal syndrome abates. *Individualized “symptom-triggered” dosing approach: Benzodiazepines are administered on a dose-by-dose basis (e.g., 25 to 100 mg of chlordiazepoxide hourly) as guided by withdrawal symptoms

BENZODIAZEPINES AND OTHER DRUGS (1)Long-acting benzodiazepines: chlordiazepoxide, clorazepate, and diazepam, have the advantage of requiring less frequent dosing.(2) Short-acting benzodiazepines: lorazepam and oxazepam are rapidly converted to inactive water-soluble metabolites that will not accumulate, thus not causing adverse effect on liver. So short-acting drugs are useful in alcoholic patients with liver disease.

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OTHER DRUGSβ-Blockers (atenolol and propranolol), α-agonists (clonidine), and antiepileptics (carbamazepine) improve signs and symptoms of alcohol withdrawal.

PREVENTION OF RELAPSEThree commonly used psychotherapeutic techniques: (1) Motivational enhancement therapy: The patients identify reasons for staying away from alcohol. (2) The 12-step facilitation therapy: The patients use the principles to help focus their attention on abstinence. (3) Cognitive behavioral coping skills therapy: The patient identifies factors which trigger to alcohol use and to help deal with the triggers when they are present.

PHARMACOTHERAPY TO PREVENT RELAPSE TO ALCOHOL USE

• The drugs disulfiram, naltrexone and acamprosate are useful for the treatment of alcohol dependence prevention.

(1) DISULFIRAM: • It is designed to prevent alcohol use by causing a severe adverse reaction when patients use alcohol. The disulfiram reaction (aldehyde syndrome) which includes flushing, nausea, vomiting, diarrhea and hypotension mediated by the inhibition of alcohol dehydrogenase resulting increase in blood levels of acetaldehyde and acetate after ingestion of alcohol.• Disulfiram is effective in reducing alcohol intake in highly motivated patients.

(2) NALTREXONE.

• Naltrexone decreases alcohol use by diminishing the euphorigenic effects of alcohol and by decreasing craving in alcohol-dependent patients.

• Alcohol-dependent patients who receive naltrexone (50 mg/day) are more likely to remain abstinent and the effects persist after discontinuation of treatment.

• Side effects of naltrexone may be self-limited nausea in about 10% of patients. Dose-related hepatotoxicity seen with high-dose naltrexone (300 mg/day).

• Mild liver enzyme abnormalities are not a contraindication but patients should be followed with repeat liver enzymes.

• Patients with acute hepatitis or liver failure should not be given naltrexone

(3) ACAMPROSATE (N-ACETYLHOMOTAURINE )• It reduces the incidence of relapse and prolongs abstinence.• It decreases drinking frequency and reduces relapse drinking in abstinent alcoholics. • It acts in a dose-dependent manner (1.3 to 2 g/day} and appears to have efficacy similar to that of naltrexone. • Acamprosate generally is well tolerated by patients, with diarrhea being the main side effect. • Concomitant use of disulfiram increases effectiveness of acamprosate, without adverse drug interaction • The mechanism of action of acamprosate is obscure. It modulates CNS neurotramitters. • It causes competitive inhibition of NMDA receptors) and affects the inhibitory GABA system.

MAJOR PATHWAYS OF ETHANOL METABOLISM

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lead to impotence in men. Increased blood alcohol concentrations lead to decreased sexual arousal, increased ejaculatory latency, and decreased orgasmic pleasure

Other Pharmacologic Treatments to Prevent Relapse • Other medications that have shown promise include ondansetron,6 bromocriptine, and sodium valproate. • Other drugs have shown possible benefits in patients with concurrent depression (e.g., fluoxetine) or anxiety (e.g., buspirone) or no effect (e.g., lithium).

• Many female alcoholics complain of decreased libido, decreased vaginal lubrication, and menstrual cycle abnormalities. • An increased reaction time, diminished fine motor control, impulsivity, and impaired judgment become evident when the concentration of ethanol in the blood is 20 to 30 mg/dl. More than 50% of persons are grossly intoxicated by a concentration of 150 mg/dl. In fatal cases, the average concentration is about 400 mg/dl.

ION CHANNELS AND ALCOHOLA number of ion channels in the CNS are sensitive

to ethanol, including representatives of the ligand-gated and G protein-coupled receptor families and voltage-gated ion channels. Substantial biochemical, electrophysiological, and behavioral data implicate the GABAA receptor as an important target for the in vivo actions of ethanol.

Bicuculline, a GABAA-receptor antagonist, and antagonists at the benzodiazepine-binding site on GABAA receptors decrease alcohol consumption in animal models.

The administration of the GABAA-receptor agonist muscimol into specific regions of the limbic system in rats can substitute for ethanol in discrimination studies.

• Neuronal nicotinic acetylcholine receptors also may be prominent molecular targets of alcohol. Both enhancement and inhibition of nicotinic acetylcholine receptor function have been reported depending on the concentrations of ethanol tested. There is an association between nicotine exposure (smoking) and alcohol consumption in human beings.

Tolerance is defined as a reduced behavioral or physiological response to the same dose of ethanol

• There is an increase in NMDA-receptor function after chronic alcohol ingestion that may contribute to the CNS hyperexcitability and neurotoxicity seen during ethanol withdrawal.

• Physical dependence is demonstrated by the elicitation of a withdrawal syndrome when alcohol consumption is terminated. • The symptoms and severity are determined by the amount and duration of alcohol consumption and include sleep disruption, autonomic nervous system (sympathetic) activation, tremors, and in severe cases, seizures. • In addition, two or more days after withdrawal, some individuals experience delirium tremens, characterized by hallucinations, delirium, fever, and tachycardia. Delirium tremens can be fatal. • Another aspect of dependence is craving and drug-seeking behavior, often termed psychological dependence.

• Alcoholism "runs in families“: shows that alcohol dependence has a genetic component. • It generally is in the range of 40% to 60%, which means that environmental variables also are critical for individual susceptibility to alcoholism.• This has been attributed to genetic differences in alcohol- and aldehyde-metabolizing enzymes. • Specifically, genetic variants of ADH that exhibit high activity and variants of ALDH that exhibit low activity protect against heavy drinking. This is so because alcohol consumption by individuals who have these variants results in accumulation of acetaldehyde, which produces a variety of unpleasant effects.• The genes for susceptibility to alcoholism identified in genome in humans include the dopamine D4 receptor, the 1 subunit of the GABAA receptor, and tyrosine hydroxylase, an enzyme involved in the synthesis of dopamine, norepinephrine, and epinephrine

MISCELLANEOUSW DRUGS • Ondansetron, a 5-HT3-receptor antagonist and antiemetic drug reduces alcohol consumption in laboratory animals .• Ondansetron is effective in the treatment of early-onset alcoholics, who respond poorly to psychosocial treatment alone.• Ondansetron administration lowers the amount of alcohol consumed, particularly by drinkers who consume fewer than 10 drinks per day. No effect on the pharmacokinetics of ethanol. *Topiramate, a drug used for treating seizure disorders appears useful for treating alcohol dependence. • Compared with the placebo group, patients taking topiramate achieved more abstinent days and a lower craving for alcohol . • The mechanism of action of topiramate is not well understood but is distinct from that of other drugs used for the treatment of dependence (e.g., opioid antagonists), suggesting that it may provide a new and unique approach to pharmacotherapy of alcoholism.

The volume ofdistribution for ethanol approximates total body water (0.5–0.7 L/kg).

At levels of ethanol usually achieved in blood, the rate of oxidationfollows zero-order kinetics, ie, it is independent of time and concentration of the drug.

• The abnormalities that have been characterized as fetal alcohol syndrome include (1) intrauterine growth retardation (2) micro-cephaly, (3) poor coordination, (4) underdevelopment of midfacial region appearing as a flattened face, and (5) minor joint anomalies. • More severe cases may include congenital heart defects and mental retardation.

Other clinical trials are focusing on: (1) 5-HT system:

(i) Selective serotonin reuptake inhibitors (SSRI) such as fluoxetine as well as

(ii) Selective serotonin receptor ligands such as buspirone, a 5-HT1A receptor partial agonist; and (iii) 5-HT2 receptor antagonist e.g. ritanserin. (2) DA receptor antagonists e.g. selective antagonists of D1 and D2 dopamine receptors being studied (3) Drugs acting through GABA and glutamate systems are also under investigation.(4) The NMDA receptor is implicated in cognitive function, including learning and memory. Blackouts "periods of memory loss - with high levels of alcohol -may be due to inhibition of NMDA receptor activation.