Alcohol ( Pharmacology and neurobiology )

1. Alcohol (Pharmacology and neurobiology) By: Dr Alia Alshanawani Dr. Ishfaq A. Bukhari Dep of Medical Pharmacology, KSU

2. Currently Alcohol ( Ethyl alcohol or ethanol) is the most commonly abused drug in the world. Alcohol in low-moderate amounts relieves anxiety & fosters a feeling of well-being/ euphoria. Alcohol abuse and alcoholism cause severe detrimental health effects such as alcoholic liver and heart disease, increased risk for stroke,chronic diarrhoea and alcohol dementia

3. Pharmacokinetic of Alcohol water-miscible molecule, completely absorbed from GIT Peak blood ethanol conc after po doses: 30 -75 min, absorption is delayed by food . Volume of distribution = Total Body Water Metabolism (in gastric mucosa & liver). 1- Oxidation of ethanol to acetaldehyde via A- ADH;; reduction of NAD+ to NADH. Mainly in liver. OR B- via microsomal ethanol oxidizing system 2- Acetaldehyde is converted to acetate via AlDH, w also reduce NAD+ to NADH. Acetate ultimately is converted to CO2 + water.

4. Alcohol Metabolism; 90-98% metabolized in liver ADHALDH CH3CH2OH  CH3CHOCH3COOH Ethanol Acetaldehyde Acetic Acid

5. Peroxisome Cytosol H2O2 NAD+ ER CAT O2 ADH MEOS NADPH Pyrazole H2O P450 NADH Aminotriazole NADP+ NAD+ Mitochondrion AlDH NADH Disulfiram (antabuse) Chlorpropamide (diabetes) Extra-hepatic tissue Hepatic Cellular Processing EtOH Acetaldehyde Acetate

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

7. Healthy Liver vs Fatty Liver • Alcohol converted to Acetaldehyde which is more toxic than alcohol  • causing Mild inflammation and Fat cell proliferation

8. Metabolism: Genetic Variation Genetic variation in alcohol metabolizing enzymes AldehydeDehydrogenase .(ALDH) Acute acetaldehyde toxicity in individuals with an inactive form of the ALDH2*2 (mitochondrial aldehydedehydrogenase 2). Associated with the ‘flushing reaction’ immediately following alcohol intake (due to increased acetaldehyde) Mostly Asian populations have ALDH2*2 allele .

9. Chronic ethanol consumption induces cytochrome P450 2E1, whic leads to ! generation of ROS + a deficiency of oxygen in ! tissues (hypoxia). • Chronic ethanol use: NAD & of NADH by ! liver. • All of these biochemical changes have been proposed to contribute to DNA damage, hepatocyte injury & liver disease. • Pyruvate is reduced to lactate to generate NAD & metabolic acidosis • This will cause hypoglycemia in malnurished alcoholics • Lactate also inhibit uric acid excretion;; hyperuricemia.

10. Hyperlipidemia & fat deposition are common in chronic alcohol use because of excess acetate & FA synthesis + direct oxidation of ethanol for energy instead of using body fat stores.

11. Effects of alcohol greatly depends on dose and frequency of use. In order of increasing dose (or number of drinks),alcohol is anxiolytic mood-enhancing sedative slows reaction time produces motor incoordination impairs judgment (making it dangerous and illegal to drive a car). At very high doses alcohol produces loss of consciousness

12. Medical complications of chronic alcoholism: • Liver disease: ! most common medical complication. Accumulated acetaldehyde: hepatotoxicity. • Fatty liver/ alcoholic steatosis (common, reversible, hepatomegaly, slight elevation in liver enzyme) • Followed by: steatohepatitis (fat, inflammation, & injury), • then hepatic cirrhosis (jaundice, ascites, bleeding & encephalopathy) & • liver failure & death within 10 yrs.

13. Alcoholic Liver Disease Normal Steatosis Cirrhosis Steatohepatitis

14. Your Healthy Liver @AMSP 2010

15. Your Liver on Alcohol @AMSP 2010

16. Hematological complication: • Iron deficiency anemia; inadequate dietary intake & GI blood loss • Hemolytic anemia; liver damage • Megaloblastic anemia; folate deficiency in chronic alcoholism,, malnutrition, impaired folate abs, & hemolysis. • Thrombocytopenia & prolong bleeding times; suppressing platelet formation • Alcohol can diminish ! production of Vit-K dependent clotting factors; due to hepatotoxic action

17. Alcohol effects on Central NTs: Alcohol causes: inhibition of NMDA (Glutamate) & activation of GABAA receptors (Rs) in brain this will lead to: - Sedative effect & CNS depression • Disruption in memory, consciousness, alertness & learning by alcohol. “Blackouts”

18. Alcohol effects on Central NTs Chronic use of alcohol leads to UP-REGULATION of NMDA-Rs & voltage-sensitive Ca Channels ;; 1- increased NMDA activity significantly Ca influx to ! nerve cells, Ca excess can lead to cell toxicity & death. (Ca related brain damage). 2- This also contribute to alcohol tolerance & withdrawalsymptoms (tremors, exaggerated response & seizures).

19. Ethanol interactions e NTs release • Ethanol enhances Dopamine (DA) release in ! “pharmacological reward” pathway • Ethanol appears to release DA from ! VTA & NAC via interactions e multiple NT Rs • Ethanol has direct excitatory actions on DA containing neurons in the VTA Ventral Tegmental Area (VTA) Nucleus accumbens (NAC) Control Dopamine Ethanol + + Dopamine

20. Alcohol as a Reinforcer: Neural Systems • Alcohol effects: • Acute, DA in NAC • Chronic,  DA in NAC  tolerance Activation of mesocorticolimbic system

21. Cont’ NTs release: Alcohol increases release of: -- DA: role in motivational behavior/ reinforcement, i.e. rewarding stimuli & contribute to addiction -- Serotonin: alcohol rewarding effects, tolerance & withdrawal 5-HT system modulates the DAergic activity of the VTA and the NAC. -- Opioid peptides; feeling of euphoria & increase ! rewarding effect of alcohol.

22. Cardiovascular: • Chronic alcohol abuse can lead to alcohol cardiomyopathy; cardiac hypertrophy, lowered ejection fraction, compromised ventricular contractility ; heart failure & degeneration. • It is a type of dilated cardiomyopathy. Due to ! direct toxic effects of alcohol on cardiac muscle, !unable to pump blood efficiently, leading to heart failure. results from: 1- alterations in contractile functions of ! heart 2- membrane disruption 3- up-regulation of voltage-dependent Ca2+ channels 4- function of mitochondia & sarcoplsmic reticulum 5- FA ethyl ester & oxidative damage.

23. Alcoholic Cardiomyopathy Control Alcoholic

24. Cardiovascular: • Arrhythmia: premature ventricular/ atrial contractions, atrial & ventricular tachycardia, atrial fibrillation & flutter. result from: cardiomyopathy, electrolyte imbalance & conduction delays induced by alc & its metabolites. • CHD: Moderate alcohol consumption: prevent CHD ( HDL) Excess drinking is associated e higher mortality risk from CHD. • HTN: ( Ca & sympathetic activity).

25. Fetal Alc Syndrome: IRREVERIBLE • Ethanol rapidly crosses placenta • Pre-natal exposure to alcohol causes: - intrauterine growth retardation, congenital malformation (wide-set eyes, microcephaly, impaired facial development) & teratogenicity - fetal growth by inducing hypoxia. - More severe cases include congenital heart defects & physical + mental retardation.

26. Fetal Alcohol Syndrome ( FAS )

27. Gastritis & ulcer diseases, Alcohol causes: • Malabs of water-soluble vit • Acute/ chronic hemorrhagic gastritis • Gastroesophageal reflux disease, esophageal bleeding (reversible). • Cancer • Excessive consumption of alc ! risk of developing cancers (tongue, mouth, oropharynx, esophagus, liver, & breast). Due to chronically irritating membranes Acetaldehyde can damage DNA & cytochrome P450 activity + stimulate carcinogenesis.

28. Pancreatitis: • Occur in heavy drinkers • Presented as severe pain + elevated amylase & lipase • Due to hyperlipidemia • Tr: parenteral analgesics, hydration & nutrition.

29. Endocrine: hypogonadism • In women: amenorrhea, anovulation, luteal phase dysfunction, hyperprolactinemia & ovarian dysfunction, infertility & spontaneous abortion + impairment fetal growth. • In men: hypogonadism, loss of facial hair, gynecomastia, muscle & bone mass, testicular atrophy & sexual impotence. .. Also alc may testesterone & inhibit pituitary release of LH.

30. Wernicke-Korsakoff syndrome is a manifestation ofthiaminedeficiency, usually as a secondary effect of alcabuse (severe alcoholism). Result from: (inadequate nutritional intake; uptake of thiamine from GIT, liver thiamine stores are due to hepatic steatosis or fibrosis). ! syndrome is a combined manifestation of 2 disorders: Wernicke's encephalopathy is ! acute neurologic disorder & is characterized by CNS depression (mental sluggishness, confusion, Coma), ocular disorder (impairment of visual acuity & retinal hge), ataxia & polyneuropathy. Korsakoff's Psychosis main symptoms areamnesia&executive dysfunction. Tr: thiamine + dextrose-containing IV fluids.

31. Acute ethanol intoxication: • CNS depression: sedation, relief anxiety, higher conc: slurred speech, ataxia, & impaired judgment • Resp depression leading to resp acidosis & coma • Death can occur from resp depression + aspiration of vomitus.

32. Significant depression of myocardial contractility • Vasodilation due to depression of vasomotor center & direct smooth muscle relaxation caused by acetaldehyde. • Volume depletion, hypothermia & Hypotension • Hypoglycemia occur in conjunction e reduced CHs intake & malnourished alcoholics.

33. Acute Ethanol Intoxication • Supportive therapy till metabolism clear body to low levels • Hypotension/hypovolumia → IV fluids • Artificial respiration • Hypoglycmia:IV gluc • Coma: lavage, naloxone (opioid antagonist)

34. Elevated acetaldehyde during ethanol intoxication causes: • N & headache • Sensitivity rxs, Vasodilation & facial flushing • Increase skin temperature, • Lower BP • Sensation of dry mouth & throat • Bronchial constriction & allergic-type rxs • Euphoric effects that may reinforce alcohol consumption. • Increase incidence of GI & upper airway cancers • Liver cirrhosis.

35. Alcoholism Tolerance • ! person must drink progressively > alcohol to obtain a given effect on brain function • Tolerance develops e steady alcohol intake via: • Metabolic tolerance, hepatic enzyme induction • Functional tolerance, change in CNS sensitivity (Neuro-adaptation ) • Faster alc absorption • Tolerance appear to involve NMDA R, GABA R, 5-HT, DA in brain reward & reinforcement.

36. Alcoholism withdrawal • Alc Withdrawal occurs > 2/3 Alcohol Dependence patients • Symptoms: • Autonomic hyperactivity & craving for alcohol • Hand tremor • Insomnia, anxiety, agitation • vomiting & thirst • transient visual/ auditory illusions • Grand mal seizures (after 7-48 hr alc cessation) • Rebound supersensitivity of glutamate Rs & hypoactivity of GABAergic Rs are possibly involved

37. Alcoholism withdrawal • Chronic wks-months intake followed by stop leads to two-stage severe withdrawal: • Aforementioned symptoms after few hours • After ≥2 days delirium tremens” stage starts fatal; profuse sweating, delirium & hallucinations, intense Vasodilation, fever, severe tachycardia Possible causes: • rebound β-adrenoceptor super-sensitivity • hyperactivity of neural adaptive mechanism (neuroadaptation) no longer balance by ! inhibitory effect of alcohol & upregulation of NMDA Rs .

38. Alcohol withdrawal symptoms • withdrawal symptoms depend upon severity, rate & duration of preceding drinking period • In mild cases: hyperexcitability • In severe cases: seizures, toxic psychosis & delirium tremens. • Begin after 8 hours, Peak at day 2, Diminish at day 5, Disappear 3 - 6 months.

39. Schematic representation of ! effects of alc exposure & withdrawal.

40. in the Figure! zero line represents ! excitability of ! brain. • Short-term alcohol intake produces a depression of ! inhibitory centers of ! cerebral cortex, which results in ! initial symptoms of intoxication (euphoria, exaggerated feelings of well-being, & loss of self-control followed by sedation). • Long-term alcohol intake causes ! initial decrease e tolerance that occurs during continued exposure to alc. • Removal of alcohol causes a rebound stimulatory effect, increasing excitability in ! nervous system.

41. Management of alcoholism withdrawal • Substituting a long-acting sedative hypnotic drug for alc & then tapering ! dose. • Such as BDZs (chlor-diazepoxide, diazepam) OR short acting are preferable (lorazepam) • 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.

42. Cont’ Management: • Clonidine; inhinbits enhanced symp NT release • Propranolol; inhibits ! action of exaggerated symp activity • Naltrexone; po, an opioid antagonist, e weak partial agonist activity, reduce psychic craving for alcohol in abstinent patients & reduce relapse • Acamprosate; a weak NMDA-R antagonist & GABA activator, reduce psychic craving.

43. Fluoxetine in Alcoholics Transient reduction in drinking Reduction in drinking in alcoholics with a family history of Alcohol Dependence 5-HT and Human Alcohol Consumption ---- Reduced 5-HIAA levels

44. For adjunctive Tr of alc dependence: Disulfiram therapy: 250 mg daily • Disulfiram blocks hepatic AlDH, this will increase bld acetaldehyde conc. • If alc + disulfiram = extreme discomfort & disulfiram ethanol rx: VD, flushing, hotness, cyanosis, tachyC, dyspnea, palpitations & throbbing headache. • Disulfiram-induced symptoms render alcoholics afraid from drinking alc.

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

46. Alcohol and drug interactions • Increase in the risk of developing a major GI bleed or an ulcer when NSAIDs are used with alcohol • Increases hepatotoxicity when Acetaminophen and alcohol used concurrently (chronic use). • Alcohol increases the risk of respiratory and CNS depression effects of narcotic drugs (codeine and methahdone).