Alcohol Lecture Notes (PHAR 230) PDF

PHAR 230  Alcohol Known for > 8000 years Refers to “Ethanol” although there are different types Before sanitation, alcoholic beverages were safer to antiseptic ↳ as drink than water Today, w...

PHAR 230  Alcohol Known for > 8000 years Refers to “Ethanol” although there are different types Before sanitation, alcoholic beverages were safer to antiseptic ↳ as drink than water Today, widely consumed & socially accepted The most commonly abused drug in the world > - used to use ethanol > now - use isopropyl  Chemical Structure Organic compound consists of: OH– & Functional group saturated Examples: – Methanol: CH3OH – Ethanol: C2H5OH – Propan-2-ol (isopropyl alcohol): C3H7OH – Ethane-1,2-diol (ethylene glycol): C2H4(OH)2  Ethanol CHsOH Small molecule Produced by sugar fermentation Water–soluble found > - water in Organic solvent can dissolve lipids > - Volatile & flammable catch > - fire on Used as: – Recreational drug – Antiseptic / disinfectant – Chemical solvent – Fuel  Pharmacokinetics fabsorbed in Stomach Absorption: rapidly through GIT through blood barrier brain > will - pass Peak blood level: within 30 minutes (F>M) - volume of distribution Distribution: rapid – ­ VD close to total body water (0.5-0.7 L/kg) Crosses membranes: e.g., BBB – placenta Metabolism: liver (90%) – oxidation – 2 pathways … Excretion: – Kidney ® urine – Lungs ® breath (DUI)  Metabolic Pathways hydrogen oxidation , lose Chsolt Faldehyde-hydrogen removed lead to accumulation of ethanol as it inhibits a conol dehydrogenase -remove hydrogen oxidation reaction flushing n/V - , , dizziness MEOS: Microsomal Ethanol-Oxidizing System lead to accumulation Fomepizole: treatment of methanol or ethylene glycol poisoning of acetaldehyde as it Disulfiram: treatment of alcohol dependence inhibits aldehyde vinegar-acetic acid dehydrogenase  Metabolic Pathways Rate: – Zero order kinetics (= independent of time & concentration) 2 pathways: – Alcohol dehydrogenase (primary pathway) ® Acetaldehyde ® – MEOS (chronic alcoholism) – Acetate ® CO2 OR acetyl-CoA Acetaldehyde accumulation ® – Facial flushing, nausea, vomiting, dizziness, headache > - tachycardia > - people take alcohol to feel Mechanism of Action euphoric , it passes BBB CNS to ↑ blood brain barrier Affects several neurotransmitter systems involved in the brain’s reward pathways mainly GABA & glutamate GABAa > increase ­ GABA-mediated inhibition through GABAA receptor Pathway - = CN) depression ¯ glutamate-mediated excitation through NMDA receptor inhibition Other actions: > - increase stimulation > - decrease – ­ dopamine (DA)–mediated reward processes * 11 CVS depression – ­ endogenous opioid & cannabinoid pathways 2) ↑ dopamine ↳ respond to cannabis High dose: but also alcohol 3) I addiction – Na channel blockade, electrical stabilization & ¯ conduction of nerve action potential (direct effect) Prevents depolarization = , no action potential GABA = Gamma-aminobutyric acid – NMDA = N-methyl-D-aspartate Mechanism of Action PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum Mechanism of Action PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum Pharmacodynamics of Acute Consumption 1 CNS depression: – Chronic drinkers require higher concentrations due to tolerance Pharmacodynamics of Acute Consumption 2 Heart: – ¯ myocardial contractility – High dose: dysrhythmia Smooth muscle relaxation: to ¯ vasomotor center + acetaldehyde – Due suddenly false sensation - blood theat gushing is coming out feel warm-but and you will it is – Vasodilation ® hypothermia (heat loss) + hypotension – Uterine relaxation  Drug Interactions Additive CNS depression with other CNS depressants A speed up enzymes to break down alcohol Hepatic microsomal enzyme induction ® – ­ metabolism of drugs -can lead to acute liver damage – Generation of toxins, free radicles, H2O2 Drugs with disulfiram-like reaction: – E.g., metronidazole, trimethoprim acetaldehyde ↳ disulfiram - accumulation of Long-term Effects of Alcohol Consumption 1 CNS: physical – Tolerance, addiction & dependence – Neurotoxicity  Tolerance > - need to add more when you build tolerance May result from: – Ethanol–Induced up–regulation of a pathway Results in: – Decreased intensity – Shortened duration of action Cross tolerance with: – Sedative–hypnotics – General anesthetics * alcohol cannot be stopped be abruptly gradual , has to Dependence Addiction Psychological dependence: – Compulsion to: § Experience the rewarding effect § Avoid the withdrawal symptoms ↳ when you abruptly stop Physical dependence: ® – Withdrawal syndrome: § Mild: hyperexcitability § Severe: seizures – psychosis – delirium tremens – coma – death extreme sympathetic nervous system stimulation Hyperadrenergic state, disorientation, tremors, diaphoresis, impaired attention/consciousness & visual & auditory hallucinations Time Course of Alcohol Withdrawal Symptoms early mild symptoms : severe later symptoms more  Neurotoxicity Peripheral neuropathy Wernicke-Korsakoff syndrome: - chronic important alcohol use of for peripheral NS – Caused by thiamine (vitamin B1) deficiency – Manifestations: - give glucose § Extrinsic eye muscles paralysis - give naloxone § Ataxia > - give vitamin BI § Confusion ® encephalopathy ® coma ® death – Sequalae after treatment: § Korsakoff’s psychosis – memory loss § Impaired vision Long-term Effects of Alcohol Consumption 2 Liver: big victim to alcohol – Alcoholic fatty liver ® hepatitis ® cirrhosis ® liver failure GI: – Gastritis ® peptic ulcer & GI bleeding If > - drink on empty stomach – Chronic pancreatitis – Malabsorption CVS: long term consumption of alcohol abuse – Cardiomyopathy & HF – Dysrhythmias – atrial & ventricular – Hypertension Hematologic: Folic acid deficiency & Fe¯ anemia Abnormal immune response Long-term Effects of Alcohol Consumption 3 * with chronic alcohol use anything can happen Endocrine & metabolic: hormones ↑ levels of – ♂: Gynecomastia & testicular atrophy – Hypoglycemia diabetes > - acid – Lactic acidosis accumulation of lactic - Cancer: – Mouth, pharynx, larynx, esophagus, liver – Causes: acetaldehyde, folate metabolism changes, chronic inflammation Fetal alcohol spectrum disorders (FASDs) 4 drinking while pregnant Fetal alcohol spectrum disorders (FASDs) Group of conditions in children due to chronic maternal alcohol abuse during pregnancy Mechanism of teratogenic effect: unknown! Wide spectrum: most severe is Fetal Alcohol Syndrome (FAS) Main manifestations: doesn't develop enough brain – Growth retardation – Microcephaly – Facial features – Congenital heart defects – CNS defects …  CNS Defects in FAS Cognitive deficits: - inability to learn – E.g., learning disabilities – mental retardation Impaired motor function: – E.g., lack of coordination – impaired gross & fine motor skills Attention & hyperactivity problems (ADHD) Social skills problems lack ofskills social Epilepsy  Management of Alcohol Intoxication Treatment of acute intoxication (overdose) Management of withdrawal syndrome Treatment of alcoholism  Treatment of Acute Intoxication Prevent severe respiratory depression Aspiration of vomitus Correct electrolyte imbalances Treatment of hypoglycemia & ketoacidosis Vitamin B1 (thiamine) No antidote  Management of Withdrawal Syndrome Mild symptoms don’t need treatment Prevention of seizures, delirium & dangerous dysrhythmias: – Vitamin B1 (thiamine) – Correct electrolytes – e.g., K, Mg, PO4 > - Sedative – Benzodiazepines cause depression ans without > - alcohol § Long-acting – e.g., diazepam § In liver disease: short acting – e.g., lorazepam  Treatment of alcoholism Rehabilitation & psychological therapy Naltrexone: similar to naloxone makeaddicted opioids sure pt not to – Long-acting opioid antagonist – blocks mu (µ) receptors Acamprosate: stimulate GABA pathway inhibit glutamate pathway – ¯ NMDA receptor & ­ GABAA receptor Disulfiram: ­­­ flushing, nausea, vomiting, dizziness, headache, … and drinks if pt takes disulfiram – alcohol it will present with more side effects which will make pt HATE alcohol I short term solution Alcoholism Drug Therapy: General Consideration All three drugs are administered orally Greduce addiction Both Naltrexone & Acamprosate help reduce craving Disulfiram makes the patient hates drinking Precautions while using Naltrexone: – Patient should not be opioid dependent (opioid withdrawal) – Don’t combine with Disulfiram (both are hepatotoxic) Acamprosate is poorly absorbed from GIT  Methanol (Wood Alcohol) Uses: – Solvent, fuel, windshield, antifreeze, … (HCOH) Absorption: don't drink this will be , but if absorbed ingested through : – GIT, skin, respiratory system Metabolism: Toxicity: – Due to formaldehyde & formate firreversible acid formic = toxic > - optic dystrophy nerve – Effect: visual disturbances ® blindness ® anion gap metabolic acidosis ® sudden cessation of respiration ® death – Treatment: fomepizole or ethanol (antidotes) – IV  Ethylene Glycol Polyhydric alcohol Has sweet taste Uses: toxic – Solvent, heat exchangers, antifreeze Metabolism: toxic Toxicity: – Due to glycolaldehyde & oxalic acid – Effect: CNS excitation ® CNS depression Kidney damage liver ® anion gap metabolic acidosis ® renal & hepatic failure ® death + – Treatment: fomepizole or ethanol (antidotes) – IV life saving