Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Alcohol By: Dr Alia Alshanawani Dep of Medical Pharmacology, KSU 1 Today, alc is widely consumed Alc, like other sedative/ hypnotic drugs, in lowmoderate amounts relieves anxiety & fosters a feeling of well-being/ euphoria. It is ! most commonly abused drug in ! world. 2 Alcohol: - Ethyl alcohol (ethanol) • PK: Alc is a water-soluble molecule, complete absorbed from GIT Peak bld ethanol conc after po doses: 30 -75 min, 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, w also reduce NAD+ to NADH. Acetate ultimately is converted to CO2 + water. 3 Hepatic Cellular Processing EtOH Peroxisome H2O2 CAT H2O Aminotriazole Cytosol O2 NADPH NADP+ ER MEOS P450 NAD+ ADH NADH Pyrazole Acetaldehyde NAD+ Mitochondrion AlDH NADH Disulfiram (antabuse) Acetate Extra-hepatic tissue Chlorpropamide (diabetes) Hepatic Ethanol Metabolism ADH RATE-LIMITING STEP Alcohol Acetaldehyde NAD+ NADH Chronic intake→ induction of CYP2E1 NAD+ AlDH NADH Acetyl CoA Acetate Citric Acid Cycle 5 Fatty Acid synthesis Energy Fatty liver • Chronic ethanol consumption induces cytochrome P450 2E1, w leads to ! generation of ROS & RNS + 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. 6 • Hyperlipidemia & fat deposition are common in chronic alc use bec of excess acetate & FA synthesis + direct oxidation of ethanol for energy instead of using body fat stores. 7 • 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) & - 8liver failure & death within 10 yrs. Alcoholic Liver Disease Steatosis Normal Steatohepatitis 9 Cirrhosis 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 abs, & hemolysis. Thrombocytopenia & prolong bleeding times; suppressing platelet formation Alc can diminish ! production of Vit-K dependent clotting factors; hepatotoxicity. 10 • Alcohol effects on Central NTs: Alc causes inhibition of NMDA (Glutamate) & activation of GABAA Rs in brain this will lead to: - Sedative effect & CNS depression - Disruption in memory, consciousness, alertness & learning by alc. “Blackouts” 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, Ca excess can lead to cell tox & death. (Ca related brain damage). 2- This also contribute to alc tolerance & withdrawal symptoms (tremors, exaggerated response & seizures). 11 Ethanol interactions e NTs release • Ethanol enhances 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 12 + + Dopamine 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 -- Opioid peptides; feeling of euphoria & increase ! rewarding effect of alc. 13 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 Ca2+ chs 4- function of mitochondia & sarcoplsmic reticulum 5- FA ethyl ester & oxidative damage. 14 Alcoholic Cardiomyopathy Control Alcoholic 15 • Arrhythmia: premature ventricular/ atrial contractions, atrial & ventricular tachyC, atrial fibrillation & flutter. result from: cardiomyopathy, electrolyte imbalance & conduction delays induced by alc & its metabolites. • CHD: Moderate alc consumption: prevent CHD ( HDL) 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 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. 17 • - Gastritis & ulcer diseases, Alc 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 18 carcinogenesis. • Pancreatitis: - Occur in heavy drinkers - Presented as severe pain + elevated amylase & lipase - Due to hyperlipidemia - Tr: parenteral analgesics, hydration & nutrition. 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 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 & executive dysfunction . 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 + aspiration of vomitus. 22 • 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 e reduced CHs intake & malnourished alcoholics. 23 Acute Ethanol Intoxication • Supportive therapy till metabolism clear body to low levels Hypotension/hypovol umia → IV fluids Artificial respiration Intoxication Mild signs Ethanol level <500 mg/L (0.05%) ≤ 1000 mg/L (0.1%) Frequent Psychomotor Impairment Hypoglycmia:IV gluc Psychomotor 1500 Coma: lavage, Impairment in mg/L(0.15%) naloxone everyone Severe/ anesthe2500 mg/L sia & coma (0.25%) Death (respiratory 5000 mg/L 24 depression) (0.5%) • 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. 25 Alcoholism Tolerance • ! person must drink progressively > alc to obtain a given effect on brain function • Tolerance develops e 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. 26 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) Rebound supersensitivity of glutamate Rs & hypoactivity of GABAergic Rs are possibly involved 27 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 VD, fever, severe tachyC Possible causes: rebound β-adrenoceptor super-sensitivity hyperactivity of neural adaptive mechanism (neuroadaptation) no longer balance by ! inhibitory effect of alc & upregulation of NMDA Rs . 28 Alc withdrawal symptoms In conclusion, degree of 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. 29 ! zero line represents ! excitability of ! brain. • Short-term alc intake produces a depression of ! inhibitory centers of ! cerebral cortex, w 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 e tolerance that occurs during continued exposure to alc. • Removal of alc causes a rebound stimulatory effect, increasing excitability in ! nervous system. 30 Schematic representation of ! effects of alc exposure & withdrawal. 31 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 32causes respiratory depression & hypotension. • Cont’ Management: - Clonidine; inh enhanced symp NT release - Propranolol; inh ! action of exaggerated symp activity - Naltrexone; po, an opioid antagonist, e 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. 33 • 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. 34