Alcohol abuse & pharmacodynamics final

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pharmacodynamics of ethanol, alcohol abue signs and symptoms and their treatment

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Alcohol abuse & pharmacodynamics final

  1. 1. ALCOHOL DYNAMICS AND ABUSE BY DR. SYED SALEEM AHMEDPROFESSOR OF PHARMACOLOGY AND CLINICAL THERAPEUTICS
  2. 2. ALCOHOL ABUSE AND DEPENDENCE• A primary chronic disease with genetic psychosocialand environmental factors: (1) Often progressive andfatal & characterized by impaired control over drinking(2)Preoccupation with the alcohol (3) Use of alcoholdespite future consequences and (4)Distortions ofthinking 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%.
  3. 3. PHARMAOKINETICS AND ALCOHOLISM• Women have lower levels of gastric alcoholdehydrogenase (enzyme responsible for metabolizingalcohol), they experience higher blood alcoholconcentrations than men.• The absorption of alcohol can be affected by otherfactors, including the presence of food in the stomachand the rate of alcohol consumption.• By means of metabolism in the liver, alcohol isconverted to acetaldehyde and acetate .• Metabolism is proportional to body weight• A genetic variation in a significant proportion of theAsian population alters the structure of an aldehydehydrogenase isoenzyme, resulting in aldehyde syndrome
  4. 4. ALCOHOL WITHDRAWAL• The clinical manifestations of alcohol withdrawalinclude hyperactivity resulting in tachycardia anddiaphoresis.• Patients also experience tremulousness, anxiety, andinsomnia. More severe alcohol withdrawal can result innausea and vomiting, which can exacerbate metabolicdisturbances.• Perceptual abnormalities, including visual and auditoryhallucinations and psychomotor agitation, are commonmanifestations of more moderate-to-severe alcoholwithdrawal.• Grand mal seizures commonly occur during alcoholwithdrawal, although they do not generally requiretreatment beyond the acute withdrawal phase.
  5. 5. ALCHOL WITHDRAWAL SYDROME• Tremor is typically among the earliest symptoms and can occurwitahin 8 hours of the last drink. Symptoms of tremulousnessand motor hyperactivity peak within 24 to 48 hours. Althoughmild tremor involves the hands, more severe tremors caninvolve the entire body and greatly impair a variety of basicmotor functions.• Perceptual abnormalities begin within 24 to 36 hours after thelast drink and resolve within a few days.• The withdrawal seizures are generalized tonic-clonic and mostoften occur within 12 to 24 hours after reduction of alcoholintake. •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.
  6. 6. 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 withoutevidence of any chronic medical manifestations for many years.• As time goes on, however, the likelihood that one or more ofthese manifestations will occur increases considerably.• The primary organ systems involved include the nervoussystem, cardiovascular system, liver, gastrointestinal system,pancreas, hematopoietic system, and endocrine system.• Patients may have the risk of a variety of malignancies, such ashead and neck, esophageal, and liver cancers.• Excessive alcohol use often causes significant psychiatric andsocial morbidity.
  7. 7. 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 dementiaresembling Alzheimer’s disease .• The deficiency of vitamins such as thiamine may have a majorimpact in terms of promoting alcoholic dementia and severecognitive dysfunction, as is seen in Korsakoff’s syndrome.• Alcohol also causes a polyneuropathy that can present withparesthesias, numbness, weakness, and chronic pain.• As with the CNS, peripheral nervous system effects are thoughtto be caused by a combination of the direct toxicity of alcoholand nutritional deficiencies.• A small proportion (<1%) of patients with alcohol dependencemay develop midline cerebellar degeneration, which presents asan unsteady gait.
  8. 8. (2) CARDIOVASCULAR SYSTEM• The most common cardiovascular complications of chronicalcohol consumption are cardiomyopathy, hypertension, andsupraventricular arrhythmias.• Alcoholic cardiomyopathy can present clinically in a mannersimilar to other causes of heart failure. It is the most commoncause of non-ischemic cardiomyopathy in Western countries (44%).• Alcoholic cardiomyopathy also responds to conventionaltreatments for heart failure. Abstinence from alcohol can result insignificant improvement.• Increasing levels of alcohol consumption also are associated withsystolic and diastolic hypertension .• The most common arrhythmias associated with chronic alcoholuse include atrial fibrillation and supraventricular tachycardia withacute intoxication and withdrawal.• Alcoholic cardiomyopathy also is associated with arrhythmias, inparticular, ventricular arrhythmias.
  9. 9. (3) LIVER• Alcohol abuse is the major cause of morbidity and mortalityfrom liver disease.• Factors that predispose to early liver disease include thequantity and duration of alcohol exposure, female gender, andmalnutrition.• The clinical manifestations includes acute fatty liver, alcoholichepatitis, and cirrhosis.• Fatty liver can be asymptomatic or associated with nonspecificabdominal discomfort ad generally improves with abstinencefrom alcohol. Alcoholic hepatitis can present as an asymptomatic conditionidentified through abnormalities in liver enzymes or as an acuteepisode with abdominal pain, nausea, vomiting, and fever.• Patients with alcoholic hepatitis have high levels of aspartateaminotransferase in the blood and elevated levels of γ-glutamyltransferase. The hepatitis improves with abstinencefrom alcohol.
  10. 10. (4) HEPATIC CIRRHOSIS• It is a major cause of death in the United States.• Although patients are often asymptomatic, patientswith more advanced cirrhosis may present with a varietyof symptoms and signs, including jaundice, ascites, andcoagulopathy.• Cirrhosis is also associated with gastrointestinalbleeding from esophageal varices.• Although there is some controversy about the use ofliver transplantation to treat patients with alcoholiccirrhosis, physicians believe that patients in establishedrecovery are good candidates for liver transplantation incase of advanced cirrhosis.
  11. 11. (5) GASTROINTESTINAL DISEASE.• Chronic alcohol use is associated with a variety of esophagealproblems, including esophageal varices, Mallory-Weiss tears, andsquamous cell carcinoma of the esophagus.• The risk of squamous cell carcinoma is increased further inpatients who smoke tobacco and drink alcohol.• Acute alcoholic gastritis presents with abdominaldiscomfort, nausea, and vomiting. (6) PANCREAS• The risk of pancreatitis in individuals with alcohol dependence isapproximately four times that in the general population.• It may present with severe abdominalpain, nausea, vomiting, fever, and hypotension and can be life-threatening.• Individuals with recurrent acute pancreatitis may developchronic pancreatitis, which presents with chronic abdominalpain, malabsorption, weight loss, and malnutrition.
  12. 12. (7)HEMATOPOIETIC SYSTEM• The anemia can be multifactorial (e.g., blood loss, nutrientdeficiency, 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 , alcoholicgastritis or bleedig esophageal varices.• Dietary folate deficiency causes megaloblastic anemias .• Alcohol also has a direct toxic effect on the bone marrow, which canlead to sideroblastic anemia that resolves after abstinence .• Alcohol can suppress megakaryocyte production and causesthrombocytopenia manifesting as petechiae or bleeding .The plateletcounts usually returning to normal after cessation of alcohol intake.• Alcohol-related immune dysfunction, as evidenced by decreasedproduction and function of white blood cells and derangement inhumoral and cell-mediated immunity causes higher risk for infectiousdiseases, such as pneumonia and tuberculosis.• The hypersplenism with cirrhosis contributes to the increased risk of
  13. 13. (8) MALIGNANCIES.• Alcohol intake has been associated with upperdigestive, respiratory, and liver malignancies.• Alcohol use is associated with squamous cell carcinomas of theesophagus and of the head and neck.• Either heavy alcohol use or smoking individually increases therate of oropharyngeal cancer by about 6 to 7 times that of thegeneral population, whereas the risk for people with both riskfactors is about 40 times.• Patients with alcohol-induced liver disease with a history ofhepatitis B/C are at increased risk for hepatocellular carcinoma• Chronic alcohol use also associated with malignancies of thebreast , prostate , pancreas, cervix, lung and colon. Hormonalmechanisms and direct carcinogenic effects of alcohol have beenpostulated as causes of this association.• The cervical cancer with alcohol dependence may be due toalcohol-associated with high-risk sexual behaviors .
  14. 14. (9)OTHER MEDICAL ISSUES.• Gout has been associated with alcohol abuse, and flares can occurat 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 presumablyowing to alcoholic induced disruption in hypothalamic-pituitarydysfunction, gonadal toxicity, and impaired hepatic metabolism ofcirculating 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.
  15. 15. (11) PSYCHIATRIC ISSUES• The prevalence of anxiety disorders is about 40%, andof affective disorders is about 30%.• Antisocial personality disorder is also more common.These psychiatric problems are more prevalent duringperiods of heavy drinking and withdrawal.• All patients with alcohol use disorders require carefulscreening for psychiatric illnesses. Effective treatment ofunderlying psychiatric disorders may result in improveddrinking behaviors. (12) OTHER BEHAVIORAL AND PSYCHOSOCIAL ISSUES• There may domestic injuries, trauma, motor vehicleaccidents, and burns . Tobacco and other drug abuse aremore prevalent in people with alcohol problems than inthe general population.
  16. 16. Both acute and chronic alcohol use can lead toimpotence in men. Increased blood alcoholconcentrations lead to decreased sexualarousal, increased ejaculatory latency, anddecreased orgasmic pleasure
  17. 17. USE OF STANDARDIZED SCREENING INSTRUMENTS• Many standardized questionnaires have been developed todetect alcohol abuse and dependence.• The two questionnaires that have been evaluated mostextensively in medical settings are the CAGE (Cutdown, Annoyed, Guilty, and Eye opener) questionnaire and theAlcohol Use Disorder Identification Test (AUDIT).• The CAGE questionnaire includes four questions and is scoredby giving 1 point for each positive response. Given that theword ever is used in each CAGE question, by definition thisinstrument is designed to detect lifetime alcohol problems anddoes not distinguish between lifetime problems and currentproblems.• To screen for alcohol abuse and dependence, the CAGE has asensitivity of 43 to 94% and a specificity of 70 to 97% when acutoff score of 2 is used to indicate a “positive” result.
  18. 18. 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 isdecreased 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
  19. 19. BENZODIAZEPINES AND OTHER DRUGS (1)Long-acting benzodiazepines: chlordiazepoxide,clorazepate, and diazepam, have the advantage ofrequiring 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. OTHER DRUGS β-Blockers (atenolol and propranolol), α-agonists (clonidine), and antiepileptics (carbamazepine) improve signs and symptoms of alcohol withdrawal.
  20. 20. PREVENTION OF RELAPSEThree commonly used psychotherapeutic techniques: (1) Motivational enhancement therapy: The patients identify reasons for staying awayfrom 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 toalcohol use and to help deal with the triggers whenthey are present.
  21. 21. PHARMACOTHERAPY TO PREVENT RELAPSE TO ALCOHOL USE• The drugs disulfiram, naltrexone and acamprosate are usefulfor the treatment of alcohol dependence prevention. (1) DISULFIRAM:• It is designed to prevent alcohol use by causing a severeadverse reaction when patients use alcohol. The disulfiramreaction (aldehyde syndrome) which includes flushing, nausea,vomiting, diarrhea and hypotension mediated by the inhibitionof alcohol dehydrogenase resulting increase in blood levels ofacetaldehyde and acetate after ingestion of alcohol.• Disulfiram is effective in reducing alcohol intake in highlymotivated patients.
  22. 22. (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
  23. 23. (3) ACAMPROSATE (N-ACETYLHOMOTAURINE )• It reduces the incidence of relapse and prolongsabstinence.• It decreases drinking frequency and reduces relapsedrinking in abstinent alcoholics.• It acts in a dose-dependent manner (1.3 to 2 g/day} andappears 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 ofacamprosate, without adverse drug interaction• The mechanism of action of acamprosate is obscure. It modulates CNS neurotramitters.• It causes competitive inhibition of NMDA receptors) andaffects the inhibitory GABA system.
  24. 24. MAJOR PATHWAYS OF ETHANOL METABOLISM A
  25. 25.
  26. 26. Other Pharmacologic Treatments to Prevent Relapse• Other medications that have shown promise includeondansetron,6 bromocriptine, and sodium valproate.• Other drugs have shown possible benefits in patientswith concurrent depression (e.g., fluoxetine) or anxiety(e.g., buspirone) or no effect (e.g., lithium).
  27. 27. • Many female alcoholics complain of decreased libido, decreased vaginal lubrication, and menstrual cycle abnormalities.• An increased reaction time, diminished fine motorcontrol, impulsivity, and impaired judgment become evidentwhen the concentration of ethanol in the blood is 20 to 30mg/dl. More than 50% of persons are grossly intoxicated by aconcentration of 150 mg/dl. In fatal cases, the averageconcentration is about 400 mg/dl.
  28. 28. ION CHANNELS AND ALCOHOL A number of ion channels in the CNS are sensitiveto ethanol, including representatives of the ligand-gatedand G protein-coupled receptor families and voltage-gated ion channels. Substantialbiochemical, electrophysiological, and behavioral dataimplicate the GABAA receptor as an important target forthe in vivo actions of ethanol. Bicuculline, a GABAA-receptor antagonist, andantagonists at the benzodiazepine-binding site onGABAA receptors decrease alcohol consumption inanimal models. The administration of the GABAA-receptor agonistmuscimol into specific regions of the limbic system inrats can substitute for ethanol in discrimination studies.
  29. 29. • Neuronal nicotinic acetylcholine receptors also may be prominent molecular targets of alcohol.Both enhancement and inhibition of nicotinicacetylcholine receptor function have been reporteddepending 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.
  30. 30. • Physical dependence is demonstrated by the elicitation of awithdrawal syndrome when alcohol consumption is terminated.• The symptoms and severity are determined by the amount andduration of alcohol consumption and include sleep disruption,autonomic nervous system (sympathetic) activation, tremors, andin severe cases, seizures.• In addition, two or more days after withdrawal, some individualsexperience delirium tremens, characterized by hallucinations,delirium, fever, and tachycardia. Delirium tremens can be fatal.• Another aspect of dependence is craving and drug-seekingbehavior, often termed psychological dependence.
  31. 31. • 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- andaldehyde-metabolizing enzymes.• Specifically, genetic variants of ADH that exhibit high activityand variants of ALDH that exhibit low activity protect againstheavy drinking. This is so because alcohol consumption byindividuals who have these variants results in accumulation ofacetaldehyde, 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
  32. 32. MISCELLANEOUSW DRUGS• Ondansetron, a 5-HT3-receptor antagonist and antiemetic drugreduces alcohol consumption in laboratory animals .• Ondansetron is effective in the treatment of early-onsetalcoholics, who respond poorly to psychosocial treatment alone.• Ondansetron administration lowers the amount of alcoholconsumed, particularly by drinkers who consume fewer than 10drinks per day. No effect on the pharmacokinetics of ethanol. *Topiramate, a drug used for treating seizure disorders appearsuseful for treating alcohol dependence.• Compared with the placebo group, patients taking topiramateachieved more abstinent days and a lower craving for alcohol .• The mechanism of action of topiramate is not well understoodbut is distinct from that of other drugs used for the treatment ofdependence (e.g., opioid antagonists), suggesting that it mayprovide a new and unique approach to pharmacotherapy ofalcoholism.
  33. 33. The volume of distribution for ethanol approximates total body water (0.5–0.7 L/kg). At levels of ethanol usually achieved in blood, the rate of oxidation follows zero-order kinetics, ie, it is independent of time and concentration of the drug.• The abnormalities that have been characterized as fetal alcohol syndromeinclude (1) intrauterine growth retardation (2) micro-cephaly, (3) poorcoordination, (4) underdevelopment of midfacial region appearing as a flattenedface, and (5) minor joint anomalies.• More severe cases may include congenital heart defects and mental retardation.
  34. 34. 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 asbuspirone, 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 cognitivefunction, including learning and memory. Blackouts"periods of memory loss - with high levels of alcohol -may be due to inhibition of NMDA receptor activation.

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