By: Dr Alia AlShanawani Dep of Medical Pharmacology, KSU 1 May 2011

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

Alc: Ethyl alcohol (ethanol) PK: water-soluble molecule, complete absorbed from GIT Peak blood ethanol conc. after po doses: min, absorption is delayed by food. 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, which also reduce NAD + to NADH. Acetate ultimately is converted to CO 2 + water. 3

4 Alc Metabolism; 90-98% metabolized in liver ADH AlDH CH3CH2OH  CH3CHO  CH3COOH Ethanol Acetaldehyde Acetic Acid

Mitochondrion Peroxisome 5 EtOH Acetaldehyde Acetate Cytosol ER NADH CAT H2O2H2O2 H2OH2O AlDH NAD + NADH MEOS NADP + NADPH O2O2 P450 Extra-hepatic tissue Pyrazole Disulfiram (antabuse) Chlorpropamide (diabetes) Aminotriazole

Hepatic Ethanol Metabolism 6 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

Healthy Liver vs Fatty Liver 7

Chronic ethanol consumption induces cytochrome P450 2E1, which leads to ! generation of ROS & RNS + hypoxia. Chronic ethanol use: NAD & of NADH by ! liver. All 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. 8

Hyperlipidemia & fat deposition are common in chronic alc use bec of excess acetate & fatty acid (FA) synthesis + direct oxidation of ethanol for energy instead of using body fat stores. 9

Effects of alc greatly depends on dose & frequency of use. In order of increasing dose (or number of drinks), alc is anxiolytic mood-enhancing sedative slows reaction time produces motor incoordination impairs judgment (making it dangerous & illegal to drive a car). At very high doses alc produces loss of consciousness. 10

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 enz) - Followed by: steatohepatitis (fat, inflammation, & injury), - then hepatic cirrhosis (jaundice, ascites, bleeding & encephalopathy) & - liver failure & death within 10 yrs. 11

Alcoholic Liver Disease Steatosis SteatohepatitisCirrhosis Normal 12

13 Your Healthy Liver

14 Liver on Alcohol

inhibition of NMDA (Glutamate) Rs & activation of GABA A Rs in brain this will lead to: - Sedative effect & CNS depression - Disruption in memory, consciousness, alertness & learning by alc “Blackouts”. 15 Alcohol effects on Central NTs

Chronic use of alc leads to UP-REGULATION of NMDA- Rs & voltage-sensitive Ca Ch ;; 1- increased NMDA activity significantly Ca influx to ! nerve cells, excess Ca can lead to cell toxicity & death (Ca related brain damage). 2- This also contribute to alc tolerance & withdrawal symptoms (tremors, exaggerated response & seizures). 16 Cont’ Alc effects on Central NTs:

Control Ethanol enhances DA release in ! “pharmacological reward” pathway Ethanol appears to release DA from ! VTA & NAC via interactions with multiple NT Rs Ethanol has direct excitatory actions on DA containing neurons in the VTA Ethanol enhances DA release in ! “pharmacological reward” pathway Ethanol appears to release DA from ! VTA & NAC via interactions with multiple NT Rs Ethanol has direct excitatory actions on DA containing neurons in the VTA Nucleus accumbens (NAC) Ethanol interactions with NTs release Ethanol ++ Ventral Tegmental Area (VTA) Dopamine 17

Alcohol as a Reinforcer: Neural Systems 18 Activation of mesocorticolimbic system Alcohol effects: Acute,  DA in NAC Chronic,  DA in NAC  tolerance

Cont’ NTs release: Alc also increase release of: -- DA: role in motivational behavior/ reinforcement, i.e. rewarding stimuli & contribute to addiction -- Serotonin: alc rewarding effects, tolerance & withdrawal 5-HT system modulates the DAergic activity of the VTA & the NAC. -- Opioid peptides; feeling of euphoria & increase ! rewarding effect of alc. 19

Cardiovascular: - Chronic alc abuse can lead to alc cardiomyopathy that leads to cardiac hypertrophy, lowered ejection fraction, compromised ventricular contractility & COP;; heart failure & degeneration. - It is a type of dilated cardiomyopathy. Due to ! direct toxic effects of alc on hrt muscle, ! hrt is unable to pump bld efficiently, leading to hrt failure. results from: 1- alterations in contractile functions of ! hrt 2- membrane disruption 3- up-regulation of voltage-dependent Ca 2+ chs 4- function of mitochondia & sarcoplsmic reticulum 5- FA ethyl ester & oxidative damage. 20

Alcoholic Control Alcoholic Cardiomyopathy 21

Arrhythmia: premature ventricular/ atrial contractions, atrial & ventricular tachyC, atrial fibrillation & flutter. result from: cardiomyopathy, electrolyte imbalance & conduction delays induced by alc & its metabolites. Coronary Heart Disease: Moderate alc consumption: prevent CHD ( HDL) Excess drinking is associated e higher mortality risk from CHD. HTN: ( Ca & sympathetic activity). 22

Fetal Alc Syndrome (FAS): IRREVERIBLE Ethanol rapidly crosses placenta Pre-natal exposure to alc causes: - intrauterine growth retardation, congenital malformation (wide-set eyes, microcephaly, impaired facial development) & teratogenicity - fetal growth by inducing hypoxia. - More severe cases include congenital hrt defects & physical + mental retardation. 23

Fetal Alcohol Syndrome ( FAS ) 24

Gastritis & ulcer diseases, Alc causes: - Malabsorption of water-soluble vitamins - 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. 25

Hematological complication:  Iron deficiency anemia; inadequate dietary intake & GI bld loss  Hemolytic anemia; liver damage  Megaloblastic anemia; folate deficiency in chronic alcoholism,, malnutrition, impaired folate absorption, & hemolysis.  Thrombocytopenia & prolong bleeding times; suppressing platelet formation  Alc can diminish ! production of Vit-K dependent clotting factors; hepatotoxicity. 26

Pancreatitis: - Occur in heavy drinkers - Presented as severe pain + elevated amylase & lipase - Due to hyperlipidemia - Tr: parenteral analgesics, hydration & nutrition. 27

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. 28

Wernicke-Korsakoff syndrome is a manifestation of thiamine deficiency, usually as a secondary effect of alc abuse (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 are amnesia & excutive dysfunction. Tr: thiamine + dextrose-containing IV fluids. 29

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. 30

Cont’ Acute ethanol intoxication: Significant depression of myocardial contractility VD due to depression of vasomotor center & direct smooth muscle relaxation caused by acetaldehyde. Volume depletion, hypothermia & Hypotension Hypoglycemia occur in conjunction with reduced CHs intake & malnourished alcoholics. 31

Acute Ethanol Intoxication Supportive therapy till metabolism clear body to low levels  Hypotension/hypovolu mia → IV fluids  Artificial respiration  Hypoglycmia:IV gluc  Coma: lavage, naloxone Ethanol level Intoxication <500 mg/L (0.05%) Mild signs ≤ 1000 mg/L (0.1%) Frequent Psychomotor Impairment 1500 mg/L(0.15%) Psychomotor Impairment in everyone 2500 mg/L (0.25%) Severe/ anesthe- sia & coma 5000 mg/L (0.5%) Death (respiratory depression) 32

Elevated acetaldehyde during ethanol intoxication causes: - N & headache - Sensitivity rxs, VD & facial flushing - Increase skin temperature, - Lower BP - Sensation of dry mouth & throat - B.constriction & allergic-type rxs - Euphoric effects that may reinforce alc consumption. - Increase incidence of GI & upper airway cancers - Liver cirrhosis. 33

Alcoholism Tolerance ! person must drink progressively > alc to obtain a given effect on brain function Tolerance develops with steady alc 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. 34

Alcoholism withdrawal  Alc Withdrawal occurs > 2/3 Alc Dependence patients  Symptoms:  Autonomic hyperactivity & craving for alc  Hand tremor  Insomnia, anxiety, agitation  N, V & thirst  transient visual/ auditory illusions  Grand mal seizures (after 7-48 hr alc cessation) hypoactivity of GABAergic Rs  Rebound supersensitivity of glutamate Rs & hypoactivity of GABAergic Rs are possibly involved. 35

Alcoholism withdrawal  Chronic wks-months intake followed by stop leads to two-stage severe withdrawal: Aforementioned symptoms after few hours delirium tremens” After ≥2 days delirium tremens” stage starts fatal; profuse sweating, delirium & hallucinations, intense VD, fever, severe tachyC Possible causes: β-adrenoceptor super-sensitivity rebound β-adrenoceptor super-sensitivity hyperactivity of neural adaptive mechanism (neuroadaptation) no longer balance by ! inhibitory effect of alc & upregulation of NMDA Rs. 36

Alc 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 months. 37

Schematic representation of ! effects of alc exposure & withdrawal. 38

! zero line represents ! excitability of ! brain. Short-term alc 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 alc intake causes ! initial decrease with tolerance that occurs during continued exposure to alc. Removal of alc causes a rebound stimulatory effect, increasing excitability in ! nervous system. 39

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. 40

Cont’ Management: - Clonidine; inhibits enhanced sympathetic NT release that occurs during withdrawal - Propranolol; inhibit ! action of exaggerated sympathetic activity - Naltrexone; po, an opioid antagonist, with weak partial agonist activity, reduce psychic craving for alc in abstinent patients & reduce relapse - Acamprosate; a weak NMDA-R antagonist & GABA activator, reduce psychic craving. 41

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. 42

Alcohol & drug interactions Chronic uses of alc induces liver enz & increase metabolism of drugs such as propranolol & warfarin etc Acute alc use inhibits liver enz & incraeses toxicity of some drugs such as bleeding with warfarin Alc suppresses gluconeogenesis, which may increase risk for hypoglycemia in diabetic patients. 43

Cont’ Alc & drug interactions Increase in the risk of developing a major GI bleed or ulcer when NSAIDs are used with alc Increases hepatotoxicity when Acetaminophen & alc used concurrently (chronic use). Alc increases the risk of respiratory & CNS depression effects of narcotic drugs (codeine & methadone). 44