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Alcohol ( Pharmacology and neurobiology )

Alcohol ( Pharmacology and neurobiology ). Dr. Ishfaq A. Bukhari Dep of Medical Pharmacology, KSU. 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.

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Alcohol ( Pharmacology and neurobiology )

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  1. Alcohol (Pharmacology and neurobiology) 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 Volume of distribution = Total Body Water Metabolism (in gastric mucosa & liver). 1- Oxidation of ethanol to acetaldehyde via ADH;;. Mainly in liver. 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. Cytosol NAD+ ER O2 ADH MEOS NADPH P450 NADH NADP+ NAD+ Mitochondrion AlDH NADH Disulfiram (antabuse) Chlorpropamide (diabetes) Extra-hepatic tissue Hepatic Cellular Processing EtOH Acetaldehyde Acetate

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

  7. Metabolism: Genetic Variation Genetic variation in alcohol metabolizing enzymes AldehydeDehydrogenase .(ALDH) Acute acetaldehyde toxicity, associated with the ‘flushing reaction’ immediately following alcohol intake (due to increased acetaldehyde) Mostly Asian populations have genetic variation.

  8. Chronic ethanol consumption induces cytochrome P450 2E1, whic leads to ! generation of recative oxygen specie (ROS) + a deficiency of oxygen in ! tissues (hypoxia). • contribute to DNA damage, hepatocyte injury & liver disease. • . Hyperlipidemia & fat deposition are common in chronic alcohol • because of excess acetate & FA synthesis + direct oxidation of ethanol for energy instead of using body fat stores

  9. 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

  10. Medical complications of chronic alcoholism: • Liver disease: ! most common medical complication. Accumulated acetaldehyde: hepatotoxicity. • Fatty liver/ alcoholic steatosis ,then hepatic cirrhosis (jaundice, ascites, bleeding & encephalopathy) & • liver failure & death within 10 yrs. Cardiovascular: • Chronic abuse can lead to alcohol cardiomyopathy; cardiac hypertrophy, lowered ejection fraction, compromised ventricular contractility ;. Due to ! direct toxic effects of alcohol on cardiac muscle.

  11. Alcoholic Liver Disease Normal Steatosis Cirrhosis Steatohepatitis

  12. Your Healthy Liver @AMSP 2010

  13. Your Liver on Alcohol @AMSP 2010

  14. 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-Kdependent clotting factors; due to hepatotoxic action

  15. 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: Excess drinking is associated e higher mortality risk from CHD. • HTN: ( Ca & sympathetic activity).

  16. 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.

  17. Fetal Alcohol Syndrome ( FAS )

  18. 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).

  19. 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.

  20. Wernicke-Korsakoff syndrome is a manifestation ofthiaminedeficiency,(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 ; acute neurologic disorder ( CNS depression, mental sluggishness, confusion, Coma), impairment of visual acuity & retinal hge, ataxia & polyneuropathy. Korsakoff's Psychosis main symptoms areamnesia&executive dysfunction.(cognitive and behavioral) Tr: thiamine + dextrose-containing IV fluids.

  21. 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

  22. 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.

  23. 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 ) • Tolerance appear to involve NMDA R, GABA R, 5-HT, DA in brain reward & reinforcement.

  24. 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”

  25. 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).

  26. 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.

  27. 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

  28. 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

  29. 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.

  30. 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 (note alcohol increase endogenous opiates that produce dependence) • Acamprosate; a weak NMDA-R antagonist & GABA activator, reduce psychic craving.

  31. 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

  32. For adjunctive Tr of alc dependence: Disulfiramtherapy: 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.

  33. 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

  34. 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).

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