Alcohol and the Brain Dr. : Asmaa Fady MD., MSC, M.B, B.Ch.. اسم ورقم المقرر – Course Name and No. 6/29/2019

Learning objectives: By the end of the lecture, the student should: Describe the pharmacological actions of alcohol Describe the pharmacokinetic profile of alcohol Describe the development of intoxication symptoms of alcohol Describe how alcohol affects various neurotransmitters in the brain. Identify various toxicity of alcohols at different organs level Describe the addictive nature of alcohol and its mechanism Identify alcohol withdrawal symptoms and their management. Identify clinically relevant drug interactions with alcohol Hazards of alcohol in pregnancy اسم ورقم المقرر – Course Name and No. 6/29/2019

Pharmacokinetics of alcohol Administration, absorption & distribution: * Drinking ethanol traditionally has been the most common route of administration, although recently the inhalation of aerosolized ethanol has gained popularity. Ethanol is absorbed from the stomach and duodenum, and food slows and decreases absorption. Peak ethanol levels are generally achieved in 20 minutes to 1 hour of ingestion. اسم ورقم المقرر – Course Name and No. 6/29/2019

Pharmacokinetics of alcohol Metabolism: Ethanol is metabolized by alcohol dehydrogenase to acetaldehyde and then by aldehyde dehydrogenase to acetate in the liver. build up of acetaldehyde leads to “flushing response” Excretion: *5-15% excreted un-metabolized through exhaled breath, sweat, urine. Ethanol Acetaldehyde Acetate CO2 + H2O Alcohol Dehydrogenase Aldehyde اسم ورقم المقرر – Course Name and No. 6/29/2019

Affects of alcohol on neurotransmitters of the brain. After crossing the blood-brain barrier, alcohol affects several neurotransmitter systems: Potentiate effect of GABA CNS depression. block the release of excitatory neurotransmitters N-Methyl-D- aspartate and thus decrease glutamate CNS depression. D2 Dopamine receptors (excitatory neurotransmitter) are stimulated resulting in Euphoria. ethanol increase endogenous endorphins release (morphine like neurotransmitters)  alcohol actually increases the serotonin levels in the brain, which is one of the reasons for the addicting effect of alcohol.

Pharmacological action of alcohol (mechanism of action) 1. CNS Effects 1. increase GABA, which is the inhibitory neurotransmitter and causes sedation. 2. block the release of excitatory neurotransmitters N-Methyl-D- aspartate (NMDA). Both (1 & 2) will lead to Descending CNS depression. 3. D2 Dopamine receptors are stimulated and endorphins are released, resulting in Euphoria. 4. Inhibition of antidiuretic hormone secretion (ADH)  Diuresis. 5. Depression of vasomotor center VM Peripheral vasodilatation hypotension and false sensation of heat while the temperature is low. 6. Respiratory Centre depression RC  hypoxia 6/29/2019

Pharmacological action of alcohol (mechanism of action) 2. Cardiovascular effects If one drunk 1-3 drinks per day (Moderate) this would decrease mortality from (coronary Artery Disease), increase HDL levels, and decrease platelet aggregation. However, larger amounts cause  increased Blood pressure and may precipitate Coronary atherosclerotic disease **Hypotension also occurs and is due to Vasodilation and ADH depression. اسم ورقم المقرر – Course Name and No. 6/29/2019

Pharmacological action of alcohol (mechanism of action) 3. Stomach HCl Secretion is:  Stimulated at <20%  Inhibited from 20-30%   Stomach irritation followed by gastritis occurs at levels >40%. اسم ورقم المقرر – Course Name and No. 6/29/2019

Pharmacological action of alcohol (mechanism of action) 4. Liver Ethanol causes fatty change in liver. This change is reversible, and caused by impairment in lipid metabolism and mobilization of peripheral fat. 5. Kidney Alcohol causes diuresis via the inhibition of ADH secretion. 6. Impotence it provokes the desire but the performance is decreased due to impotence and testicular atrophy. 7. Labor is inhibited via decrease in oxytocin secretion. اسم ورقم المقرر – Course Name and No. 6/29/2019

Intoxication symptoms of alcohol (toxic dose: 5 gm/kg for adults ) Alcohol poisoning signs and symptoms include: Confusion. Defective in judgment of time and place. Gait is not that steady Seizures. Slow irregular respiration (less than eight breaths a minute) Blurred vision, diplopia and nystagmus. Hiccough due to: Myoclonic contraction of the diaphragm.

Intoxication symptoms of alcohol (toxic dose: 5 gm/kg for adults ) Vomiting results from: *Central emetic effect of acetaldehyde. **Peripheral emetic effect Gastric irritation by the concentrated alcoholic beverage. Flushing due to cutaneous vasodilatation which produces false sensation of heat while the body temperature is low. Finally and Due to inhibition of medullary centers and spinal cord  coma, shock (cardiogenic, vasoplegic, hypovolemic). اسم ورقم المقرر – Course Name and No. 6/29/2019

Toxicity of alcohols at different organs level Tissue toxicity of alcohol is a consequence of its metabolism to acetaldehyde, and oxidant substances. Acetaldehyde and oxidants are highly reactive molecules that can damage DNA, proteins and lipids leading to impairment of organ function and carcinogenesis . 

Toxicity of alcohols at different organs level 1- Gastro – intestinal: Irritation Achlorhydria Malabsorption Cancer esophagus 2- Liver: Chronic ethanol feeding damages the hepatic mitochondria by increasing mitochondrial DNA (mtDNA) oxidation. increased levels of circulating endotoxins and pro-inflammatory cytokines that affect liver function. Prolonged excessive Ethanol insult causes damage throughout the liver resulting diffuse fibrous scar formation that compresses neighboring cells resulting in Cirrhosis. Liver passes into 4 stages: (Steatosis Hepatitis Cirrhosis Liver failure (SHCL)

Toxicity of alcohols at different organs level 3-Pancreas Chronic ethanol ingestion causes pancreatitis. Mechanisms of pancreatic affection: 1- due to the effect on intra-pancreatic digestive enzyme activation and lysosomal enzyme synthesis which contribute to the development of pancreatic injury. 2- Non-oxidative metabolism of ethanol resulting in the formation of fatty acid ethyl esters (FAEEs) in pancreas

Toxicity of alcohols at different organs level 4- heart Cardiac enlargement (Cardiomyopathy and hypertrophy) Congestive heart failure arrhysthmias. Hypertension. Beri- Beri disease: (thiamin Vit. B1 deficiency) Wet: cardiovascular disease: Wet beriberi affects the cardiovascular system resulting in a fast heart rate, shortness of breath, and leg swelling.

Toxicity of alcohols at different organs level 5- brain Cortical atrophy which is attributed to nutritional deficiencies especially thiamine and manifested by: Korsakoffs psychosis: Amnesia Memory loss (short memory) Inability to learn (irreversible) Wernick's encephalopathy. Encephalitis haemorrhagica: small areas of hemorrhage necrosis in hypothalamus and wall of ventricles Dry Beri Beri اسم ورقم المقرر – Course Name and No. 6/29/2019

Toxicity of alcohols at different organs level 6- kidneys Upon one-week ethanol administration, swelling of glomeruli and tubules, proliferation of mesangial cells. After two-month administration, ethanol metabolites- protein products and hyaline in tubular epithelial cells are observed. after six months of ethanol administration Atrophy of tubular epithelial cells, urinary casts are observed. اسم ورقم المقرر – Course Name and No. 6/29/2019

Toxicity of alcohols at different organs level 7-testes Affects spermatogenesis and testicular function. There is a marked reduction of the sperm forward motility and increase in the number of spermatozoa with morphological abnormalities ( abnormal forms). اسم ورقم المقرر – Course Name and No. 6/29/2019

Mechanism of addiction: drinking alcohol causes the release of naturally occurring feel-good opioids known as endorphins in the brain. The consumption of alcohol increases the release rate of dopamine & serotonin, thereby inducing feelings of happiness and euphoria. Alcohol consumption inhibits glutamate receptor activity, which results in calmness and reduced anxiety. The feelings of euphoria combined with reduced anxiety create a false sense of security from depression in drinkers.

Withdrawal symptoms of alcohol Excitatory/inhibitory amino acid imbalance Hyper excitability Seizures Delirium Tremens (DTs) Delirium tremens (DTs) is the most severe form of ethanol withdrawal manifested by altered mental status (global confusion) and sympathetic overdrive (autonomic hyperactivity), which can progress to cardiovascular collapse. DTs is a medical emergency with a high mortality rate, making early recognition and treatment essential. 

Withdrawal symptoms of alcohol Delirium Tremens (DTs) 5% of patients develop it and a 35% mortality rate if untreated Tachycardia - Tremors Increased body Temperature - Hallucinations Hypertension - Sweating Psychomotor agitation - Loss of ability to Control muscle movement Confusion Cardiovascular collapse and death Disorientation - altered mental status Sleep disorders Dysfunctional monoamine systems Depression اسم ورقم المقرر – Course Name and No. 6/29/2019

Management of withdrawal symptoms of alcohol: Benzodiazepines: Benzodiazepines (BZ’s) are a class of sedative medications widely prescribed to treat anxiety, insomnia, seizures and other symptoms. Antiepileptics: the antiseizure medications carbamazepine (Tegretol) and valproic acid (Depakene) have been used successfully to treat Alcohol withdrwal for many years. Antidepressants Causal direction between alcoholism and depression unclear May treat underlying motivation to drink, or reduce depression as withdrawal symptom. Disulfiram is contraindicated.

Alcohol Drug Interactions Inhibition: •Chronic alcohol consumption induces phenytoin breakdown. Potentiation: •Alcohol enhances the effects of the sedative agents (benzodiazepines) such as drowsiness, sedation Specific interaction: e.g. disulfiram (Antabuse) :Interferes with alcohol metabolism (inhibits aldehyde dehydrogenase enzyme). Used in ttt of alcohol addiction. Toxic effects: Alcohol consumption increases associated risk of gastrointestinal with NSADs bleeding. Indirect effect: Acute alcohol intake may increase anticoagulation (prevention of blood clots) by decreasing warfarin metabolism; chronic alcohol ingestion decreases anticoagulation by increasing warfarin metabolism. اسم ورقم المقرر – Course Name and No. 6/29/2019

Hazards of alcohol in pregnancy The most serious risk during pregnancy is fetal alcohol spectrum disorders (FASD). FASD is the leading known cause of mental retardation

FASD The sole cause of FASD is women drinking alcoholic beverages during pregnancy. Alcohol is a teratogen (something that interferes with development of fetus) “Of all the substances of abuse (including cocaine, heroin, and marijuana), alcohol produces by far the most serious neurobehavioral effects in the fetus.” —IOM Report to Congress, 1996

Fetal Alcohol Spectrum Disorders

اسم ورقم المقرر – Course Name and No. 6/29/2019