1. Alcohol and the brain Prof. Hanan Hagar Dr. Ishfaq A. Bukhari Medical Pharmacology Unit, KSU 1

2. Ethyl alcohol (ethanol)  Ethyl alcohol (ethanol) is the most commonly abused drug in the world. Pharmacokinetics  is a small lipophilic molecule  is water-miscible molecule  Readily crosses all biological membranes  completely absorbed from GIT  volume of distribution = Total Body Water 2

3. Pharmacokinetics of ethanol  metabolized in gastric mucosa & liver (90%).  Oxidation of ethanol to acetaldehyde via alcohol dehydrogenase or cyt-p450 (CYP2E1).  Acetaldehyde is converted to acetate via acetaldehyde dehydrogenase which also reduces NAD + to NADH.  Acetate ultimately is converted to CO 2 + water.  Excreted unchanged in urine (2-8%).  Excretion unchanged via lung (basis for breath alcohol test). 3

4. 4 Alcohol Metabolism CH3CH2OH (Ethanol) NAD+ Alcohol dehydrogenase (ADH) NADH CH3CHO (Acetaldehyde) more toxic than alcohol NAD+ Acetaldehyde dehydrogenase (ALDH) NADH CH3COOH (Acetic acid)

5. Mitochondrion Peroxisome Hepatic Cellular Processing of alcohol Ethanol Acetaldehyde Acetate Cytosol ER ADH NAD + NADH CAT H2O2H2O2 H2OH2O AlDH NAD + NADH NADP + NADPH O2O2 CYP450 Extra-hepatic tissue

6. Pharmacokinetics of ethanol  Crosses placenta and excreted in milk  Rate of elimination is zero-order kinetic (not concentration-dependent) i.e. rate of elimination is the same at low and high concentration.  Alcohol is enzyme inhibitor (P450 2E1) in acute alcohol consumption and enzyme inducer in chronic alcoholics. 6

7.  Acute alcohol consumption inhibits CYP450 2E1 so metabolized drugs as (phenytoin & tolbutamide slowly).  In chronic alcoholics: Alcohol induces CYP450 2E1, which leads to significant increases in ethanol metabolism (Tolerance) & the clearance of other drugs eliminated by the microsomal enzymes. 7

8. Metabolism: Genetic Variation Aldehyde Dehydrogenase (ALDH)  Asian populations have ALDH genetic deficiency.  develop “Acute acetaldehyde toxicity” after alcohol intake characterized by nausea, vomiting, dizziness, vasodilatation, headache and flushing.  mimicked by disulfiram (used for chronic alcoholics)

9. Mechanism of action of alcohol  is a CNS depressants  has no specific receptors  affects a large number of membrane proteins that are involved in signaling pathways as neurotransmitter receptors for amines, amino acids, opioids; Ca2+ ion channels. 9

10. Alcohol effects on central neurotransmitters Acute alcohol causes:  Activation of GABAA receptors in brain leading to CNS depression  Inhibition of glutamate receptors (NMDA) leading to disruption in memory, consciousness, alertness, learning. 10

11. Alcohol effects on central neurotransmitters Chronic use of alcohol leads to up-regulation of NMDA receptors & voltage-sensitive Ca Channels (Ca influx to nerve cells) leading to alcohol tolerance & withdrawal symptoms (tremors, exaggerated response & seizures). 11

12. Pharmacological actions of alcohol: In low-moderate amounts (CNS):  relieves anxiety, euphoria (feeling of well-being).  Sedation, hypnosis  Slurred speech, ataxia (motor incoordination)  Impaired judgment  Loss of consciousness CVS  Myocardial contractility depression  Vasodilatation due to vasomotor center depression & direct smooth muscle relaxation caused by acetaldehyde At high blood concentrations  it induces coma, respiratory depression, and death 12

13. Acute ethanol intoxication: -CNS depression: -Sedation, relief anxiety -Slurred speech, ataxia, impaired judgment -Respiratory depression: leading to respiratory acidosis & coma -CVS depression -Myocardial contractility depression -Hypotension -Volume depletion, hypothermia -Death can occur from respiratory depression. 13

14. Elevated acetaldehyde during ethanol intoxication causes: -Euphoric effects that may reinforce alcohol consumption. -Nausea & headache -Vasodilatation & facial flushing -Increase skin temperature (hyperthermia) -Lower BP -Sensation of dry mouth & throat -Bronchial constriction -Increase incidence of GI & upper airway cancers -Liver cirrhosis. 14

15. Alcohol abuse & alcoholism: Chronic alcohol consumption results into (alcoholism) and may cause severe detrimental health effects such as alcoholic liver and heart disease, increased risk for stroke, alcohol dementia. 15

16. Medical complications of chronic alcoholism Liver:  The most common medical complication  accumulated acetaldehyde hepatotoxicity.  Fatty liver/ alcoholic steatosis due to acetyl CoA accumulation & increased FA synthesis & direct oxidation of ethanol for energy instead of using body fat stores. Hyperlipidemia & fat deposition are common in chronic alcohol use  Alcoholic hepatitis  Hepatic cirrhosis: jaundice, ascites, bleeding, encephalopathy.  Irreversible liver failure. 16

17. 17 Healthy Liver Liver in chronic alcoholics

18. Healthy Liver vs Fatty Liver 18 Normal liverFatty liver

19. 19 Alcoholic Liver Disease Steatosis Steatohepatitis Cirrhosis Normal

20. Hepatic Ethanol Metabolism 20 ADH Acetaldehyde Acetate Acetyl CoA Citric Acid Cycle Fatty Acid synthesis Energy Alcohol NAD + NADH AlDH NAD + NADH RATE-LIMITING STEP Chronic intake→ induction of CYP2E1 Fatty liver

21. Cardiovascular System: Chronic alcohol abuse can lead to Cardiomyopathy -Degeneration of myocardium (due to direct toxic effects of alcohol on cardiac muscles) -Cardiac Hypertrophy -Congestive heart failure. -Arrhythmia (due to electrolyte imbalance and conduction delays induced by alcohol & its metabolites). -Hypertension: due to Ca & sympathetic activity. 21

22. Hematological complication:  Iron deficiency anemia (due to inadequate dietary intake & GI blood loss).  Megaloblastic anemia: (due to folate deficiency, malnutrition, impaired folate absorption).  Hemolytic anemia.  Thrombocytopenia (suppressing platelet formation, prolong bleeding times).  Decreased Vitamin-K dependent clotting factors production (due to hepatotoxic action). 22

23. Fetal Alcohol Syndrome: Irreversible Ethanol rapidly crosses placenta Pre-natal exposure to alcohol causes: - Intrauterine growth retardation (due to hypoxia) -Congenital malformation (teratogenicity): -Microcephaly -Impaired facial development -Congenital heart defects -Physical and mental retardation. 23

24. Fetal Alcohol Syndrome ( FAS )

25. G.I.Tract Diarrhea, weight loss, and Malnutrition  Gastritis, hemorrhagic esopahgitis, ulcer diseases, pancreatitis (due to direct toxic action on epithelium)  Gastroesophageal reflux disease, esophageal bleeding (reversible).  Mal-absorption of water-soluble vitamins  In heavy drinkers : increased risk of oral and esophageal cancer. 25

26. Endocrine system: (Hypogonadism) In women: ovarian dysfunction, amenorrhea, anovulation, hyperprolactinemia &, infertility. In men: (hypogonadism), loss of facial hair, gynecomastia, muscle & bone mass, testicular atrophy & sexual impotence. due to inhibition of luteinizing hormone (LH), decrease in testosterone, estradiol, progesterone. 26

27. Endocrine system: Hypoglycemia due to impaired hepatic gluconeogenesis. Ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone 27

28. Nervous System  Physiological and psychological tolerance  Dependence  Addiction  Neurologic disturbances 28

29. Wernicke-Korsakoff syndrome It is a combined manifestation of 2 disorders: Wernicke's encephalopathy: acute neurologic disorder characterized by confusion, coma, polyneuropathy, ataxia (motor incoordination), ocular disorder (impairment of visual acuity) Korsakoff's psychosis: amnesia & cognitive and behavioral dysfunction. Cause : thiamine deficiency due to: inadequate nutritional intake decreased uptake of thiamine from GIT decreased liver thiamine stores Treated: thiamine + dextrose-containing IV fluids. 29

30. Alcoholism Tolerance Tolerance can develops due to: Metabolic tolerance: due to induction of liver microsomal enzymes. Functional tolerance (Pharmacodynamic ): due to change in CNS sensitivity (Neuro-adaptation ). 30

31. Alcoholism withdrawal symptoms depend upon severity, duration of preceding drinking period.  Autonomic hyperactivity & craving for alcohol  Vomiting & thirst  Tremors, anxiety, agitation, insomnia  transient visual/ auditory illusions  Grand mal seizures (after 7-48 hr alcohol cessation)  delirium tremens”  delirium tremens” profuse sweating, delirium, intense vasodilatation, severe tachycardia, fever, violent behavior, hallucinations.  Super-sensitivity of glutamate Rs & hypo-activity of GABAergic Rs are possibly involved. 31

32. Management of alcoholism withdrawal -Substituting alcohol with a long-acting sedative hypnotic drug then tapering the dose. -Benzodiazepines as (chlordiazepoxide, diazepam) or lorazepam that is preferable (shorter duration of action). -Efficacy: IV/ po -Manage withdrawal symptoms & prevent irritability, insomnia, agitation & seizures. -Dose of BDZs should be carefully adjusted to provide efficacy & avoid excessive dose that causes respiratory depression & hypotension. 32

33. -Clonidine & Propranolol: inhibits the action of exaggerated sympathetic activity -Naltrexone: (an opioid antagonist with weak partial agonist activity), reduces psychic craving for alcohol. -Acamprosate: a weak NMDA-R antagonist & GABA activator, reduce psychic craving. 33

34. For adjunctive treatment of alcohol dependence: Disulfiram therapy: 250 mg daily blocks hepatic AlDH, this will increase blood level of acetaldehyde. Acetaldehyde produces extreme discomfort, vomiting, diarrhea, flushing, hotness, cyanosis, tachycardia, dyspnea, palpitations & headache. Disulfiram-induced symptoms render alcoholics afraid from drinking alc. 34

35. Mitochondrion Peroxisome Disulfiram action Ethanol Acetaldehyde Acetate Cytosol ER ADH NAD + NADH CAT H2O2H2O2 H2OH2O AlDH NAD + NADH MEOS NADP + NADPH O2O2 P450 Extra-hepatic tissue Pyrazole Disulfiram (antabuse) Chlorpropamide (diabetes) Aminotriazole

36. Alcohol and drug interactions Acute alcohol use causes inhibition of liver enzyme and increases toxicity of some drugs such as bleeding with warfarin Chronic uses of alcohol induces liver enzymes and increase metabolism of drugs such as propranolol and warfarin etc Alcohol suppresses gluconeogenesis, which may increase risk for hypoglycemia in diabetic patients 36

37.  Drugs (metronidazole, tolbutamide, cephalosporins) can inhibit ALDH enzyme “potential drug interactions with alcohol”. NSAIDs + alcohol: Increase in the risk of developing a major GI bleed or an ulcer. Acetaminophen + alcohol (chronic use): risk of hepatotoxicity. Narcotic drugs (codeine and methahdone) + alcohol: risk of respiratory and CNS depression. 37