DNAP707_Alcohol_2024-1.pptx

DNAP707: Pharmacology for Nurse Anesthesia Alcohol Jill Bettinger, Ph.D. Dept. of Pharmacology and Toxicology Virginia Commonwealth University [email protected] Alcohol use in the US Approximately 86% of Americans (18+) have consumed alcohol* ~70% drank in the last year*, 55% drank in the last mon...

DNAP707: Pharmacology for Nurse Anesthesia Alcohol Jill Bettinger, Ph.D. Dept. of Pharmacology and Toxicology Virginia Commonwealth University [email protected] Alcohol use in the US Approximately 86% of Americans (18+) have consumed alcohol* ~70% drank in the last year*, 55% drank in the last month* Per capita alcohol consumption up 8% since 2000 (as reported in 2019- more so now) (Martinez et al., 2019; Slater & Alpert, 2019) ~26% of Americans (18+) reported in 2019* that they had engaged in binge drinking in the last month. underage (12-20 years old): ~19% reported drinking in the last month (in 2019*) ~2% reported heavy alcohol use in the last month (in 2019*) young adults (18-22 years old): ~47% reported alcohol use in the last month (in 2019*) ~30% reported binge drinking in the last month (in 2019*) *statistics from National Survey on Drug Use and Health (2 Alcohol misuse is an enormous problem ~15% of Americans meet Alcohol Use Disorder (AUD) criteria* only ~7% of people with AUD got treatment in the last year Alcohol abuse is the 3rd leading cause of preventable death in the U.S.: -100,000 deaths / year; increasing significantly (White et al., 2020) (+28% of driving fatalities involve alcohol) - in ~20% of emergency hospital visits alcohol is a contributor ~30% of people admitted to hospital have alcohol problems - trauma / alcohol liver disease / cancer / heart disease & stroke ~33% men, ~25% women meet Alcohol Use Disorder (AUD) criteria in their lifetime Estimated U.S. financial burden: ~$250 billion/ year *JAMA Psychiatry 72 (8):757–766 One standard drink is less than you might think ½ cup many microbrews 12oz can = 1.5 drinks most accurate self-assessment image from NIAAA.NIH.gov PHARMACOKINETICS Ethanol distribution Absorbed primarily from the gastrointestinal tract Peak ethanol levels achieved quickly- within 30 minutes Food decreases the rate of absorption Tissue concentration across the body is roughly equivalent because of ethanol’s quick distribution. Tissue levels = blood levels True of CNS; EtOH readily crosses blood-brain barrier. Volume of distribution approximates total body water volume This accounts partially for the higher sensitivity of women to the same dose of EtOH, as women have lower total body water content. Ethanol metabolism Over 90% of EtOH is metabolized in liver. Most of the rest excreted in lungs and in urine. Metabolism in liver is a zero-order kinetics reaction Independent of time and concentration of drug. Average adult metabolism is approximately 7-10g EtOH/ hour (10 oz beer, 3.5 oz wine, 1 oz distilled spirits) this can be very variable between individuals Ethanol metabolism ALCOHOL DEHYDROGENASE NAD+ ETOH NADH + H+ PRIMARY mechanism >>90% NAD+ Acetaldehyde ALCOHOL DEHYDROGENASE (ADH) NADH + H+ Acetate ALDEHYDE DEHYDROGENASE (ALDH) ADH is rate limiting step availability of NAD+ is limiting exhausts NAD+ for other enzymatic reactions Ethanol metabolism ALCOHOL DEHYDROGENASE NAD+ ETOH NADH + H+ PRIMARY mechanism >>90% NAD+ Acetaldehyde ALCOHOL DEHYDROGENASE (ADH) NADH + H+ Acetate ALDEHYDE DEHYDROGENASE (ALDH) Accumulation of NADH underlies the development of FATTY LIVER Ethanol metabolism ALCOHOL DEHYDROGENASE NAD+ NADH + H+ PRIMARY mechanism >>90% NAD+ NADH + H+ Acetaldehyde ETOH ADH Acetate ALDH responsible for vasodilation (flushing), nausea, headaches, dizziness Principally aversive. Ethanol metabolism ALCOHOL DEHYDROGENASE NAD+ NADH + H+ PRIMARY mechanism >>90% NAD+ NADH + H+ Acetaldehyde ETOH ADH Acetate ALDH DISULFIRAM (Antabuse, Absten): inhibitor of ALDH accumulation of acetaldehyde = aversive Used as a pharmacotherapy for alcoholism. Also inhibits dopamine-b-hydroxylase, in combination with vasodilation can cause hypotension and shock. Irreversibly inhibits liver microsomal drug metabolizing enzymes (CYPs) decreases metabolism of phenytoin, diazepam. Some people can still drink despite the sickness and if they drink through this it Can make them super sick Ethanol metabolism ALCOHOL DEHYDROGENASE NAD+ NADH + H+ PRIMARY mechanism >>90% NAD+ NADH + H+ Acetaldehyde ETOH Acetate ADH ALDH Other drugs can also inhibit ALDH: cause “Disulfiram-like effects” with alcohol sulfonylureas griseofulvin metronidazole cephalosporins Ethanol metabolism EtOH also activates MICROSOMAL MIXED FUNCTION OXIDASE (MEOS) CYP2E1 At normal physiological concentrations, has an overall minor effect on ethanol metabolism in humans. At high EtOH concentration, ADH pathway becomes saturated and also can deplete NAD+ stores. MEOS is independent of NAD+. HOWEVER, it does affect metabolism of other drugs by CYP2E1 = DRUG INTERACTIONS Chronic alcohol use INDUCES this pathway People with AUD who are abstinent can be resistant to drugs like barbiturates. Ethanol metabolism EtOH also activates MICROSOMAL MIXED FUNCTION OXIDASE (MEOS) CYP2E1 Chronic alcohol use INDUCES this pathway Basis of Acetaminophen toxicity Increases potential of liver damage using even high therapeutic doses of acetaminophen. CYP2E1 NAPQI is toxic. Reactive with glutathione (inactivates ROS), when glutathione is depleted, NAPQI reacts with liver proteins and causes liver cell death. Ethanol Drug Interactions EtOH also activates MICROSOMAL MIXED FUNCTION OXIDASE (MEOS) CYP2E1 ACUTE use of alcohol can inhibit metabolism of other drugs. This may occur through saturation of enzyme activity AND/OR through decreased hepatic blood flow. This is a basis of many PHARMACOKINETIC drug interactions with ethanol: phenothiazines tricyclic antidepressants sedative-hypnotic drugs PHARMACODYNAMICS Ethanol is a complicated drug Small polar molecule Distributes throughout tissues very quickly, passes BBB Passes through membranes easily Interacts with both cell surface and intracellular proteins Can occupy water pockets in many proteins, has MANY targets Can manipulate membrane fluidity (at high concentrations) The only thing similar to this is inhaled anesthetics Physiological effects of Ethanol IS A CNS DEPRESSANT Depresses the response of respiratory centers to high CO2 levels. This can lead to fatal respiratory depression. Reduces seizure threshold. Contraindicated in epileptics. Especially true during WITHDRAWAL also during extreme intoxication (causes complex) Physiological effects of Ethanol in CNS: Ethanol potentiates GABAA receptors (majority of inhibitory synaptic transmission in the brain). Positive allosteric modulation. Effect is predicted to be CNS inhibition. This is why acutely intoxicated people need less sedation? Ethanol potentiates Glycine receptors Effect is predicted to be CNS inhibition. More sensitive to pain? Need more pain meds? and Ethanol inhibits excitatory neurotransmission (at NMDA receptors) effect is predicted to be CNS inhibition Ethanol also modifies the function of many other proteins, and the physiological consequences of at least a subset of these are certainly involved in the behavioral and physical effects of ethanol. Physiological effects of Ethanol in CNS: DEVELOPMENT OF TOLERANCE & PHYSICAL DEPENDENCE This is extremely complex; we do not completely understand the mechanisms. EtOH demonstrates partial cross-dependence with barbiturates and benzodiazapines. This indicates that the GABA system is manipulated during tolerance. WITHDRAWAL from chronic alcohol in heavy drinkers – this can last several days hyperexcitability, seizures toxic psychosis delerium tremens (DTs) – autonomic instability Can be fatal about 5% of individuals with AUD undergoing acute withdrawal Physiological effects of Ethanol in CNS: DEVELOPMENT OF TOLERANCE & PHYSICAL DEPENDENCE This is extremely complex; we do not completely understand the mechanisms. Alters nervous system (central and peripheral) physiology: probably includes compensation for the effects of ethanol down regulation of inhibitory (including GABA) systems up regulation of excitatory systems PSYCHOLOGICAL Dependence Physiological effects of Ethanol Drug treatment for Alcohol Use Disorder NALTREXONE non-selective opioid receptor antagonist. Interferes with reward pathways. Used as pharmacotherapy to assist maintenance of abstinence. Good evidence that it reduces heavy drinking and promotes abstinence* evidence that allelic variation at the mu-opioid receptor gene OPRM1 predicts effectiveness of naltrexone for abstinence. *J. Addiction Medicine, June 2, 2022 Physiological effects of Ethanol Drug treatment for Alcohol Use Disorder ACAMPROSATE (N-acetyl homotaurine, Ca +2 salt) used to assist in maintenance of abstinence. Good evidence that it reduces heavy drinking and promotes abstinence* Mechanism not completely understood. Thought to help stabilize the neurotransmitter imbalances generated during chronic ethanol exposure: Antagonizes glutamatergic transmission through NMDA receptors Agonizes GABAA receptor signaling. BUT the most recent evidence strongly suggests that it is the Ca+2 that is suppressing relapse! NOT the effects on GABA or NMDA or mGluRs. (2014, Neuropsychopharm 39, 783-91) CaCl2 works just as well (2022 Neuropharmacology April 14) *J. Addiction Medicine, June 2, 2022 Treatments for Alcohol Use Disorder Emerging drugs, not yet approved for use: Ondansetron (Zofran) mainly used as an antiemetic in conjunction with breast cancer chemotherapy Selective 5-HT3 receptor antagonist. early alcoholism, people had fewer drinks/day, more days abstinent 5-HT Topiramate (Topamax) used primarily as an antiepileptic drug, or migraine therapy. Used off label to treat alcoholism. Blocks voltage-dependent Na channels, enhances GABA response at GABAA receptors, antagonizes AMPA receptors, inhibits carbonic anhydrase. Which (if any) of these is responsible for clinical activity is unknown. Na channels Baclofen (Kemstro) used as an antispasmatic in MS Mechanism of action not understood, although it does cause hyperpolarization at afferent terminal. Possible other actions, too. Generally considered to be a GABA B agonist. Conflicting clinical trial evidence. In some trials, no effect, in others, it caused a decrease in quantity, increase in abstinence, decrease in alcohol craving and withdrawal-induced anxiety. GABA B Varenicline (Chantix) used as a smoking cessation therapy. Selective a4b2 neuronal nicotinic acetylcholine receptor agonist, but inhibits binding by nicotine, and causes a significantly less strong activation than nicotine does (partial agonist). Recently reported clinical trial (2013) showed fewer heavy drinking days, fewer drinks/day, nicotinic decrease in alcohol craving. AChRs Do not memorize this Emerging drugs for possible use to treat AUD: Do not memorize this Burnette et al., 2022 Drugs 82:251-27 Emerging drugs for possible use to treat AUD: Do not memorize this Burnette et al., 2022 Drugs 82:251-27 Physiological effects of Ethanol Cardiovascular: ACUTE: Ethanol causes vasodilation- why people have flushing metabolite acetaldehyde causes smooth muscle relaxation EtOH also affects CNS vasomotor center. - this can lead to hypothermia Physiological effects of Ethanol Cardiovascular: Moderate consumption can help HDL/LDL ratio This is somewhat controversial; not all studies agree on this increase Also, it is not clear that changing this ratio with EtOH causes health benefits Physiological effects of Ethanol Cardiovascular: Chronic consumption of high concentrations of EtOH: cardiomyopathy alcoholic-dilated cardiomyopathy (ACM) EtOH is synergistic with other heart risk factors arrhythmias EtOH induces cell death in muscle tissue, & cellular remodeling; can = fibrosis Physiological effects of Ethanol Cardiovascular: HYPERTENSION Acute use can increase blood pressure Chronic use (3+ drinks/day) can significantly increase blood pressure The mechanisms underlying this are probably varied and include effects on: CNS excitability baroreceptors autonomic nervous system renin-angiotensin-aldosterone system cortisol calcium in smooth muscle from M. Piano, Alcohol Research: Current Reviews Vol 38 Physiological effects of Ethanol Gastrointestinal Tract: Ethanol is a direct irritant of GI tissues. affects epithelial barrier of small and large intestines Stimulates acid secretion. Can produce corrosive gastritis. Contraindicated in ulcers. Can cause relaxation of esophageal sphincter = acid reflux this can contribute to esophageal cancer risk Physiological effects of Ethanol Liver: Hepatic disease. ~35% of chronic heavy drinkers develop severe liver disease fatty liver -> alcoholic hepatitis -> portal cirrhosis -> failure this can also cause coagulation disorders NAD+ ETOH NADH + H+ NAD+ Acetaldehyde ALCOHOL DEHYDROGENASE (ADH) NADH + H+ Acetate ALDEHYDE DEHYDROGENASE (ALDH) Accumulation of NADH underlies the development of FATTY LIVER Physiological effects of Ethanol Pancreatic disease: 70-90% of chronic pancreatitis is the result of alcohol abuse ~25% of acute pancreatitis is the result of alcohol abuse significantly increases the risk of pancreatic cancer diabetes Physiological effects of Ethanol Kidney: Ethanol decreases the secretion of ANTIDIURETIC HORMONE (Vasopressin) has the effect of increasing urine this can stress the kidneys kidneys can also be affected by alcohol’s effects on blood pressure- from cell toxicity? liver Physiological effects of Ethanol Malnutrition– estimates that more than ½ of people with AUD do not absorb enough thiamine Injury to the pancreas can decrease absorption of fat-soluble vitamins (A, D, thiamine) = MALNUTRITION. EtOH also has caloric value Enough for energy, not enough to be nutritive. Physiological effects of Ethanol Malnutrition Injury to the pancreas can decrease absorption of fat-soluble vitamins (A, D, thiamine) Wernicke-Korsakoff syndrome due to vitamin B1 (thiamine) deficiency Wernicke’s encephalopathy (degeneration): confusion, ataxia, coma, hypothermia Korsakoff’s syndrome (neuronal loss): anterograde and retrograde amnesia, confabulation Physiological effects of Ethanol Alcohol-related neurological disease Head trauma Peripheral neuropathy (both due to EtOH itself, and also kidney damage) Physiological effects of Ethanol Alcohol-related neurological disease Neuronal cell death and cortical atrophy Volume deviation from norm Cerebral white matter loss (demyelenation)- executive function GREY MATTER WHITE MATTER # drinks # drinks K biobank imaging samples of >36,000 individuals Daviet et al., 2022 Nature Communications 13:1175 Ethanol Drug Interactions EtOH demonstrates additive depressant effects with all other CNS depressant drugs. EtOH also demonstrates potentiation of the actions of many non-sedative drugs vasodilators Fetal Alcohol Syndrome and associated disorders: The leading preventable cause of intellectual disability in the Western world Estimations of prevalence vary from between 1 - 6 in 1000 live births probably MUCH higher (looking at phosphatidylethanol in dried newborn blood spots in Tx: 8.4% of samples were positive) Bakhireva et al ACER 2017 Hard to study because of the nature of the phenotype: gross morphological defects hard to confirm diagnosis extremely variable effects: Fetal Alcohol Spectrum Disorder (~ 1 in 100 live births) Molecular etiology remains unknown. image from Wikipedia.org