IVMS-CNS Depressants II /Drugs of Abuse IV-Ethanol


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IVMS-CNS Depressants II /Drugs of Abuse IV-Ethanol

  1. 1. CNS Pharmacology CNS Depressants II/Drugs of Abuse IV- Ethanol Prepared and Presented by: Marc Imhotep Cray, M.D. Professor BMS and Pharmacology Recommended Reading: Sedative Hypnotic Drugs Formative Assessment Practice question Clinical: E-Medicine Article Alcoholism NIAAA Home
  2. 2. Introduction  The objective of this lecture is to review the pharmacology and neurobiology of Alcohol, Alcohol Abuse and Alcoholism Presentation references and Resources for further research and study of the subject: National Institute on Alcohol Abuse and Alcoholism (NIAAA) http://www.alcoholmedicalscholars.org/ 2
  3. 3. Introduction(2)  Alcohol is most widely used drug in the world, and almost no other substance has been as comprehensively studied as much as alcohol, not only because it is one of the most commonly abused drugs, but also because of its unique and interesting pharmacology http://www.uspharmacist.com/index.asp?show=article&page=8_1137.htm 3
  4. 4. Introduction (3) Highlighted Focus  Outline  The first part of the lecture will review the pharmacokinetics of alcohol - aspects of absorption, distribution and metabolism - and highlight the factors contributing to the large variability in alcohol pharmacokinetics 4
  5. 5. Introduction (4) Highlighted Focus  The second part of the lecture will review the pharmacodynamics of alcohol, focusing on the CNS effects, discuss aspects of alcohol tolerance, why alcohol is an addictive substance, what neurotransmitter systems it affects, and  Organ Systems Pharmacological Effects / organo-pathology 5
  6. 6. Alcohol Pharmacokinetics Absorption  Ethanol is rapidly absorbed from stomach, small intestine and colon but the rate of absorption from the stomach is influenced by the food content  Ethanol evenly distributed throughout all fluids and tissues, after absorption  Placental permeability ensures access of ethanol to the fetus Also see notes page 6
  7. 7. Alcohol Pharmacokinetics Distribution  The distribution of alcohol is into total body water  There are gender differences in body composition, with women having a lower proportion of total body water compared to men, even if they have same weight  Thus, if a woman and a man, who both have same weight, consume the same amount of alcohol, the woman would achieve higher blood alcohol levels compared to the man 7
  8. 8. Alcohol Pharmacokinetics Metabolism:  Most ethanol molecules are oxidized, with the rate of oxidation insensitive to ethanol concentration (zero-order kinetics).  Most ethanol oxidation occurs in the liver and is catalyzed by alcohol dehydrogenase.  The product is acetaldehyde which is then converted to acetyl CoA Also see notes page 8
  9. 9. Alcohol Pharmacokinetics Metabolism(2):  To a limited extent, in humans, ethanol is also oxidized by mixed function oxidases in liver microsomal membranes  Genetic polymorphisms occur for both alcohol and aldehyde dehydrogenase Also see notes page 9
  10. 10. Alcohol Pharmacokinetics Alcohol Metabolism(3):  The removal of ethanol (alcohol) through oxidation by alcohol dehydrogenase in the liver from the human body is limited  Hence the removal of a large concentration of alcohol from blood may follow zero-order kinetics 10
  11. 11. Alcohol Pharmacokinetics Alcohol Metabolism(4):  Also the rate-limiting steps for eth common with other substances  For instance, the blood alcohol concentration can be used to modify the biochemistry of methanol and ethylene glycol  In this way oxidation of methanol to toxic formaldehyde and formic acid in the human body can be prevented by giving an appropriate amount of ethanol to a person who has ingested methanol  Note that methanol is very toxic and causes blindness and death  A person who has ingested ethylene glycol can be treated in the same way 11
  12. 12. Alcohol Pharmacodynamics  ETOH apparent stimulatory effects result from depression of inhibitory control mechanisms in the brain  Characteristic responses to alcohol include euphoria, impaired thought processes and decreased mechanical efficiency Also see notes page for Concentration- Response relationships 12
  13. 13. Alcohol Pharmacodynamics ETOH Tolerance Tolerance (definition) also see notes page for significance  Tolerance can be defined as the phenomenon of decreased effect with prolonged exposure to a drug.  When the tolerance occurs within the time course of a single exposure to the drug it is called acute tolerance.  Chronic tolerance occurs over repeated uses of the drug.  Tolerance can be metabolic (or pharmacokinetic) - due to induction of enzymes - for example, barbiturates  Tolerance can also be pharmacodynamic - due to physiological adaptation of the body to the presence of the drug - for example, most drugs of abuse 13
  14. 14. ETOH Mechanism of Action  Ethanol enhances GABA-mediated synaptic inhibition  Ethanol inhibits glutamate- activated ion channels (excitatory) (predominately the NMDA glutamate receptors at mild intoxicating ethanol concentrations.) 14
  15. 15. ETOH Mechanism of Action(2)  Ethanol may also act by affecting 5-HT3 receptors.  Activation of these receptors results in excitation of inhibitory interneurons.  Serotonin's action at the 5-HT3 receptor subtype is enhanced by ethanol Modified from http://www.chemcases.com/alcohol/alc-07.htm 15
  16. 16. Alcohol Neuropharmacology and Reinforcement Current research supports the idea that initial exposure to alcohol activates the reward pathway releasing DA in the Nucleus accumbens, which in turn sends messages to the cortex to be coded as experiences and perhaps as memories. Once coded, these experiences can influence, i.e. promote, subsequent behavior such further alcohol intake. Since these "memories" of drinking are linked to the environment in which the drinking took place, it is not surprising that the environmental cues can be important in guiding subsequent drinking behavior. Also see notes page 16
  17. 17. ETOH Drug-Drug Interactions  Ethanol enhances CNS depression caused by other sedative-hypnotics.  Ethanol interferes with metabolism of drugs that utilize the same hepatic oxidase system.  For example the clearance of phenytoin is prolonged due to competition with ethanol for the same mixed- function hepatic oxidase system.  By contrast, with chronic use, ethanol causes induction of hepatic metabolizing enzymes and can, in this case, increase clearance of many drugs (e.g. phenytoin (Dilantin), Tolbutamide (Orinase)). 17
  18. 18. ETOH Drug-Drug Interactions(2)  Chronic consumers of ethanol are susceptible to acetaminophen hepatoxicity probably due to accumulation of toxic metabolites and glutathione depletion. 18
  19. 19. ETOH Contraindications Contraindications for ethanol use:  Hepatic disease,  gastrointestinal ulcer,  cardiac or skeletal myopathy,  pregnancy,  individuals previously addicted to ethanol 19
  20. 20. ETOH Gross and Histopathology Webpath Drug Abusr Tutorial Slides  Normal liver, gross.  Fatty change of liver, microscopic.  Micronodular cirrhosis of liver, gross.  Micronodular cirrhosis of liver, microscopic.  Hepatocellular carcinoma, liver with micronodular cirrhosis, gross.  Esophageal varices, gross.  Wernicke's disease, hemorrhages in the mammillary bodies, gross. 20
  21. 21. ETOH Organ Systems: Pharmacological and Pathological Effects Central Nervous System  Acute effects  Ethanol is a CNS depressant  Depression of inhibitory CNS systems may be responsible for apparent stimulation that is observed initially.  With moderate intoxication, mood swings, outgoing, and expansive behavior occur  General impairment of statements function becomes evident with increased intoxication  Large amounts of ethanol may lead to severe (even lethal) respiratory depression  Chronic effects  Chronic and excessive ethanol use results in brain damage, memory loss, sleep disturbances.  Increased risk of seizures 21
  22. 22. Ethanol: Chronic CNS Effects Neuropsychiatric disturbances including Wernicke's encephalopathy  (Wernicke's encephalopathy is due to a nutritional thiamine deficiency  Common causes include Alcohol, chemotherapy-associated prolonged vomiting with lack of nourishment, eating disorders, elderly patients who had been living alone and who have not been maintaining adequate nutrition [Wernicke's may be precipitated in the hospital by glucose administration to patients who is deficient in thiamine] " Wernicke-Korsakoff encephalopathy. Note pigmentation of gray matter around third ventricle. Occurs with Vitamin B1 deficiency, most often in chronic alcoholics.“ image from educational materials (pathology) University of Texas (Houston) 22
  23. 23. ETOH Organ Systems: Pharmacological and Pathological Effects  Cardiovascular System  Acute Effects:  Ethanol causes a generalized vasodilation (due to both central effects and effects on the vascular bed)  Moderate doses, however, can cause a vasoconstrictive effect in the heart and brain.  In severe intoxication, cardiovascular depression occurs secondary to central vasomotor effects and respiratory depression.  Chronic Effects:  With chronic use, significant and irreversible damage to the myocardium may occur.  This effect is one of the most important causes of cardiomyopathy. 23
  24. 24. ETOH Organ Systems: Pharmacological and Pathological Effects Gastrointestinal Tract  Ethanol increases gastric secretions by (a) direct action on the stomach (may increase gastrin), (b) psychological mechanism (if the individual likes it), (c) stimulating sensory endings in the buccal and gastric mucosa  At high ethanol concentrations (80 proof [40% alcohol]), direct gastric mucosal irritation occurs resulting in congestive hyperemia and inflammation.  These concentrations can result in an erosive gastritis. 24
  25. 25. ETOH Organ Systems: Pharmacological and Pathological Effects Liver  Chronic use of ethanol promotes hepatic cirrhosis and is associated with an increased risk of cancer and drug toxicity (acetaminophen).  Acute use probably does not produce lasting hepatic changes. From: http://library.med.utah.edu/WebPath/TUTORIAL/DRUG/DRUG012.html Micronodular cirrhosis of liver, gross. 25
  26. 26. ETOH Organ Systems: Pharmacological and Pathological Effects Teratogenic effects:  Fetal alcohol syndrome consists of many dysfunction. including low IQ, microcephaly, facial abnormalities  Ethanol appears to be the most frequent cause of teratogenically-caused mental deficiency in the West. See: http://www.cdc.gov/ncbddd/fas/ 26
  27. 27. ETOH Organ Systems: Pharmacological and Pathological Effects Sexual Functions:  Inebriation interferes with coitus, decreasing sexual responsiveness in both men and women.  Chronic ethanol abuse may lead to impotence, sterility, testicular atrophy, and gynecomastia.  Feminization in males is due to both hyperestrogenization with reduced rate of testosterone production (due to hepatic damage) and by ethanol's induction of hepatic metabolizing enzymes, increasing the rate of testosterone inactivation. Renal: Increased diuresis due to reduction in ADH and hence a decrease in tubular water reabsorption. 27
  28. 28. ETOH and Disulfiram  Disulfiram  Disulfiram (Antabuse) inhibits aldehyde dehydrogenase which results, following ethanol ingestion, in an increased acetaldehyde concentration.  The resulting "acetaldehyde syndrome" consists of facial flush, headache, hypotension, marked uneasiness, confusion, vomiting and other symptoms.  These unpleasant effects are the basis of the use of disulfiram as part of the treatment of chronic alcoholism. 28
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  30. 30. Finish-THANK YOU 30
  31. 31. Drugs and Neurotransmitters & Mental Disorders Interactive Tutorials and Animation Learning Tools  Psychotropic Medications and Neurotransmitters Wisconsin Online  Alcohol and the brain from PBS  The Effect of Drugs and Disease on Snaptic Transmission Harvard Education  Nicotine Patch by Nucleus Communications  GABA Inhibition of Glutamate Bay Area Pain Medical Associates  Acute Pain Bay Area Pain Medical Associates  How Drugs Affect Neurotransmitters INMHA 31
  32. 32. Drugs and Neurotransmitters & Mental Disorders Interactive Tutorials and Animation Learning Tools  Schizophrehia UNIVERSITY OF CENTRAL LANCASHIRE  Epilepsy UNIVERSITY OF CENTRAL LANCASHIRE  Pharmacologic Action of Meth RnCeus.com  How is Pain Produced University of Edinburgh  How Much Alcohol can YOU TAke BBC  The Brain: Understanding Neurobiology Through the Study of Addiction National Institutes of Health  The Science of Addiction University of Utah, Genetic Science Learning Center  Stimulants and Antidepressants Dr. Ian Winship of the University of Alberta  Tranquilizers and CNS Depressants Dr.Ian Winship of the University of Alberta  Genetics of Addiction Genetics Science Learning Center 32
  33. 33. eMedicine Articles on Addiction  Alcohol-Related Psychosis  Alcoholism  Amphetamine-Related Psychiatric Disorders  Caffeine-Related Psychiatric Disorders  Cannabis Compound Abuse  Cocaine-Related Psychiatric Disorders  Hallucinogens  Inhalant-Related Psychiatric Disorders  Injecting Drug Use  Nicotine Addiction  Opioid Abuse  Phencyclidine (PCP)-Related Psychiatric Disorders  Sedative, Hypnotic, Anxiolyti c Use Disorders  Stimulants  Substance-Induced Mood Disorders: Depression and Mania 33