Behavioral Disinhibition

and

Progressive CNS Depression

(7)

• Behavioral disinhibition
• @ low doses of ethanol; promotes social interactions, increases sense of self confidence, removes behavioral restraints, inhibitory controls over behavior
• Progressive CNS depression
• at blood level of 25 mg/100 ml (0.025 %): impairment of concentration and judgement, some motor incoordination and impairment
• at 50 mg/100 ml (0.05%): more cognitive and motor impairments, slurred speech
• at 80-100 mg ethanol/100 ml blood (0.08-0.10%): legal definition of intoxication in many states; defects in eye movements, dysarthrias, ataxia, impaired reaction time, psychomotor abilities
• at 200-300 mg/100 ml (0.20-0.30%): acute confusional state; hypoventilation
• at approx. 300-400 mg/100 ml (0.40%): approaching lethal level; unconsciousnes
• overdose death may result from hypotension and shock with acute renal failure or from central respiratory depression

• "Alcohol in moderate amounts has psychotropic effects that people find pleasurable.  In moderate amounts, alcohol is an appetite stimulant, a tranquilizer, a euphoric and a sedative.  It tends to release the drinker from behavioral restraints and inhibitions of society and induces an enhanced sense of self esteem.”
• Dopamine release, endogenous opiods. addicting

EFFECTS OF ETHANOL ON THE CNS

(5)

•  Behavioral disinhibition
• Progressive CNS depression; impairment of motor and mental function
• NOTE:  these are more pronounced as blood alcohol levels are RISING
• Death from acute overdosage (blood levels > 400 mg/dl (0.40%) from hypotension, shock and acute renal failure or respiratory depression
• Also, the activation of nervous system can take place as interneurons might be inhibited first

The “hangover”

(3)

• An alcohol hangover is associated with a variety of symptoms that may include dehydration, fatigue, headache, nausea, vomiting, diarrhea, flatulence, weakness, elevated body temperature, hypersalivation, difficulty concentrating, sweating, anxiety, dysphoria, irritability, sensitivity to light and noise, erratic motor functions (including tremor), trouble sleeping, severe hunger, halithosis, and lack of depth perception.
•  Many people will also be repulsed by the thought, taste or smell of alcohol during a hangover.
  
• The symptoms vary from person to person, and occasion to occasion, usually beginning several hours after drinking. It is not clear whether hangovers directly affect cognitive abilities.

• Ethanol has a dehydrating effect by causing increased urine production (diuresis), which causes headaches, dry mouth, and lethargy. Dehydration also causes fluids in the brain to be less plentiful. This can be mitigated by drinking water after consumption of alcohol.
  
• Alcohol's effect on the stomach lining can account for nausea.Another factor contributing to a hangover are the products from the breakdown of ethanol via liver enzymes. Ethanol is converted to acetaldehyde by the enzyme alcohol dehydrogenase, and then from acetaldehyde to acetic acid by the enzyme acetaldehyde dehydrogenase.
  
• Acetaldehyde (ethanal) is between 10 and 30 times more toxic than alcohol itself, as well as being cocarcinogenic (not carcinogenic solely by itself) and mutagenic.These two reactions also require the conversion of NAD+ to NADH.
  
• With an excess of NADH, the lactate dehydrogenase reaction is driven to produce lactate from pyruvate (the end product of glycolysis) in order to regenerate NAD+ and sustain life.
  
• This diverts pyruvate from other pathways such as gluconeogenesis, thereby impairing the ability of the liver to supply glucose to tissues, especially the brain.
  
• Because glucose is the primary energy source of the brain, this lack of glucose contributes to hangover symptoms such as fatigue, weakness, mood disturbances, and decreased attention and concentration.
• Alcohol consumption can result in depletion of the liver's supply of glutathione and other reductive detoxification agents, reducing its ability to effectively remove acetaldehyde and other toxins from the bloodstream.
  
• Additionally, alcohol induces the CYP2E1 enzyme, which itself can produce additional toxins and free radicals.
• There are various nervous system effects: the removal of the depressive effects of alcohol in the brain probably account for the light and noise sensitivity.
• In addition, it is thought that the presence of other alcohols (such as fusel oils), by-products of the alcoholic fermentation also called congeners, exaggerate many of the symptoms (congeners may also be zinc or other metals added primarily to sweet liqueurs to enhance their flavor); this probably accounts for the mitigation of the effects when distilled alcohol, particularly vodka, is consumed instead.
• Red wines have more congeners than white wines, and some people note less of a hangover with white wine. Some individuals have a strong negative reaction to red wine, distinct from hangover, called red wine headache that can affect them within 15 minutes after drinking a single glass of red wine.
  
• The headache is usually accompanied by nausea and flushing.In alcohol metabolism, one molecule of ethanol (the primary active ingredient in alcoholic beverages) produces 2 molecules of NADH, utilizing vitamin B12 as a coenzyme. Over-consumption of ethanol may cause vitamin B12 deficiency as well

Similarities Between Hangover

and Withdrawal

• hangover is due partly to poisoning by the toxic chemicals into which alcohol is converted by the body and the other components of the alcoholic drink; partly due to dehydration and improper levels of electrolytes, blood glucose, and/or b-vitamins; and partly to the body's reaction to withdrawal from alcohol.
  
• The symptoms of a hangover are similar to those of withdrawal, namely a throbbing headache, nausea, and possible vomiting.
  
• Thus consuming more alcohol ("hair of the dog") may help by blunting some of these symptoms, but will only aggravate the symptoms once the liver breaks the alcohol down, because the body will have additional toxins to deal with.
  
• Some researchers have suggested that ethanol may help dilute other alcohols that cause many of the hangover symptoms, but no controlled studies were carried out.

Suggested Neurochemical Mechanisms

(3)

Enhancement of the action of g-aminobutyric acid (GABA) at the postsynaptic GABA-A receptor is common to all sedative-hypnotics.

(4)

• Sedative-hypnotics enhance the action of GABA to open the Cl- ion channel;
  
• this decreases neuronal activity in the postsynaptic cell.
  
• Ethanol holds the channel open longer for more Cl- ion influx. 
• especially likes delta containing subunits. Which are extracellular

TOXIC EFFECTS OF ETHANOL

Diagram

• Many chronic alcoholics are malnourished, i.e., they are deficient in vitamins and proteins.  factors contributing to this include:
• "empty calories"; formation of acetyl Co A from ethanol oxidation can provide energy stores (synthesis of ATP), without, however, providing nutrients such as proteins, fats, vitamins or minerals
• reduction in food intake is common in alcoholics

• Effects on immune function
• Compromised immune responses in alcoholics; increased susceptibility to infectious disease (e.g., hepatitis C)

• Endocrine-related effects
• Reproductive dysfunctions: inhibition of hypothalamic-pituitary-gonadal axis
• disruption of bone remodeling; osteoporosis
• increased risk of breast cancer in menopause 

• direct and indirect toxicities of ethanol on GI tract produce malabsorption of nutrients and dysfunctions in processes governing energy balance; e.g., compromised hepatic and pancreatic functions

•  A variety of neuropathological conditions are observed with chronic ethanol abuse.  These effects are believed to be due to direct toxic effects of ethanol:
• disruption of  cell membranes
• oxidative damage to neurons
• calcium-mediated damage

 and/or to indirect toxicity, esp. metabolic and

 nutritional effects (e.g., thiamine (B1) deficiency.

•  Wernicke’s Encephalopathy
• Responds to thiamine if early enough
• Korsakoff’s Syndrome
• permanent damage
• Peripheral neuropathies

CLINICAL IMPLICATION: Ethanol abuse and dependence can complicate many neurological and psychiatric conditions.

Wernicke's encephalopathy

(5)

1.  results from thiamine deficiency;

2.  acute confusional state (apathy, lethargy; inability to sustain mental  or physical activity; impaired awareness and responsiveness;  disorientation; concentration and attention deficits; memory loss)

3.  opthalmoplegia (nystagmus, ocular palsies)

4.   ataxia, gait disturbances

5.  responds to thiamine (100 mg daily)

1.   result of direct neurotoxicity; observe in approx 75% with Wernicke's.

2.   anterograde and retrograde amnesia

3.   permanent brain damage, not as responsive to vitamins

Peripheral Neuropathies,

Sensory and Motor

1.   sensory neuropathies: loss of sensation, paresthesias, neuropathic pain

2.   motor neuropathies: weakness, disturbances in gait

3.   often  respond to thiamine therapy

Effects of ethanol on the cardiovascular system are complex and dose-dependent. 

Possible Mechanism by Which Alcohol Reduces Risk of CHD

(7)

• One possible mechanism by which alcohol could reduce the risk of CHD is through its effects on blood lipids.
  
• Changes in plasma lipoprotein levels, particularly increases in high-density lipoprotein (HDL), have been associated with the protective effects of ethanol.
  
• HDL binds cholesterol and returns it to the liver for elimination or reprocessing, decreasing tissue cholesterol levels.
  
• Ethanol-induced increases in HDL-cholesterol thus could antagonize cholesterol accumulation in arterial walls, lessening the risk of infarction.
  
• Approximately half the risk reduction associated with ethanol consumption is explained by changes in total HDL levels.
  
• HDL is found as two subfractions, named HDL2 and HDL3.
  
• Increased levels of HDL2 (and possibly also HDL3) are associated with reduced ris

CARDIOVASCULAR EFFECTS
Blood Pressure 

(6)

•  Acute effects on blood pressure:
• Vasodilatation in skin, coronary arteries, gastric mucosa
• Vasoconstriction in cerebral vessels, skeletal muscle
• Effects of chronic high intake:
• Constriction in most beds
• Increased risk of hypertension, hemorrhagic stroke, esophageal varices (extremely dilated sub-mucosal veins)
• This vasodilation can make you feel warm, but can in fact reduce the core body temperature.

•  

  esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus. They are most often a consequence of portal hypertension, commonly due to cirrhosis; patients with esophageal varices have a strong tendency to develop bleeding.

•  Acute effects on the heart:
• Depression of contractility and output
• Arrhythmias
• Alcoholic cardiomyopathy with chronic high intake:
• Necrosis, fibrosis, inflammation
• Fat deposition
• approx. 50% mortality

•  At intake of 1-2 drinks/day or less, decreased mortality from coronary heart disease and ischemic stroke

•  May be due to ethanol and/or other constituents

POSSIBLE MECHANISMS OF CARDIOPROTECTIVE EFFECT

(6)

•  Increased synthesis of high density lipoprotein (HDL)
• Antithrombotic effect
• Coronary artery vasodilation
• Anti-inflammatory effects
• Ethanol per se vs. constituents of wine
• CLINICAL IMPLICATION:  “Should abstainers…be advised to consume ethanol…? The answer is no…”

Effects of 3-5+ drinks/day

(5)

•  3-5+ drinks/day (over ~ 10-yr period) associated with increased risk for:
• hypertension
• hemorrhagic stroke
• cardiac arrhythmias
• cardiomyopathy, heart failure

EFFECTS OF ETHANOL IN THE GI TRACT

(4)

•  Acutely, stimulation of gastric acid secretion in  low to moderate dose; inhibition in higher doses
• Long term, high intake, increased gastric acid secretion
• Acutely, decreased GI smooth muscle contraction
• Long term, high intake, increases propulsive waves, promotes diarrhea

•  Direct toxicity to cells in stomach and intestinal villi impairs absorption of nutrients, esp. vitamins

• Chronic high intake assoc. w/ gastritis, pancreatitis, gastric ulcers, GI tract cancers

CLINICAL IMPLICATIONS

(7)

•  Increased gastric acid secretion:
• Increased GI toxicity of NSAIDS
• Exacerbate peptic ulcer disease
• Exacerbate esophageal reflux disease and increase risk of esophageal cancer
• Increased cancer risk: gastric, pancreatic, colorectal (induction of CYP 2E1?)
• Pancreatitis: impairments of metabolic homeostasis

• cyp2E1 can cause toxic metabolites

•  Decreased carbohydrate metabolism due to increased NADH/NAD+
• Increased formation of the hepatotoxic metabolite of acetaminophen (CYP2E1)
• Increased lactate synthesis; acidosis

THE LIVER: A MAJOR SITE FOR ALCOHOL-INDUCED  INJURY

(4)

•  Alcoholic fatty liver
• Alcoholic hepatitis
• Cirrhosis
• Liver disease progression is enhanced in women.

• Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrous scar tissue as well as regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated),leading to progressive loss of liver function.
  
• Cirrhosis is most commonly caused by alcoholism, hepatitis B and C, and fatty liver disease but has many other possible causes.
•  Some cases are idiopathic, i.e., of unknown cause.Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome.
  
• Other potentially life-threatening complications are hepatic encephalopathy (confusion and coma) and bleeding from esophageal varices.
  
• Cirrhosis is generally irreversible once it occurs, and treatment generally focuses on preventing progression and complications.
  
• In advanced stages of cirrhosis the only option is a liver transplant.
• The word "cirrhosis" derives from Greek κίρῥος, meaning tawny (the orange-yellow colour of the diseased liver). While the clinical entity was known before, it was René Laennec who gave it the name "cirrhosis" in his 1819 work in which he also describes the stethoscope.

•  Alcoholic fatty liver
• reversible
• Alcoholic hepatitis
• Death of hepatocytes triggers inflammation
• Inflammatory mediators cause further cell death and initiate fibrosis to “wall off” necrotic tissue
• reversible
• Cirrhosis:  when necrosis, fibrosis is marked and liver function severely compromised
• Done deal

Alcoholic Fatty Liver, Alcoholic Hepatitis,

Cirrhosis

•  Alcoholic fatty liver (~ 30-50% incidence in chronic alcoholics)
•  Ethanol promotes lipolysis; release of free fatty acids from adipose tissue stores and uptake by the liver
•  Increase in NADH/NAD+ ratio from ethanol oxidation favors formation of triglycerides from free fatty acids and glycerol
• Ethanol interferes with release of triglycerides from cell; this results in large deposits of triglycerides in hepatocytes
• Fat-swollen hepatocytes can compress hepatic veins and contribute to development of portal hypertension and esophageal varices (see above)
• alcoholic fatty liver is is reversible; However it is believed to be the precursor for alcoholic hepatitis
• Alcoholic hepatitis (~ 20% incidence in chronic alcoholics with ~ 60% mortality)
• Ethanol itself, acetaldehyde and/or cytotoxic products from breakdown of triglycerides (see above) can damage hepatocytes
• This leads to 1) white blood cell infiltration, release of inflammatory mediators and inflammation (hepatitis), and 2) fibrosis (synthesis of collagen), which "walls off" necrotic tissue
• Fibrosis also further compresses portal blood vessels.  wall of vessels also thicken, further promoting portal hypertension
• 25-60% of alcoholics are also infected with hepatitis C, vs. 1-2 % of general population
• is reversible; however, hepatitis may be a precursor to cirrhosis. 
• Cirrhosis (~ 20% incidence with ~ 100% mortality)
• characterized by extensive necrosis and fibrosis with small nodules of normal tissue; severe compromise of normal hepatic function;
• may proceed from hepatitis, but may also directly develop without inflammation from the fatty liver. 
• normally irreversible

Advanced Cirrhosis, Hepatitis

Picture

•  INTAKE OF > 80 GRAM/DAY (MEN) AND 40 GM/DAY (WOMEN) FOR 3-5 YEARS; 80 GM IS EQUIVALENT TO:
• One six-pack beer
• One liter of wine
• One half-pint spirits

•  The same pathology is exhibited in many individuals with metabolic syndrome or Type 2 diabetes; termed Non-Alcoholic Fatty Liver Disease  and Non-Alcoholic Steatohepatitis
• Chronic ethanol abuse would obviously exacerbate these conditions. 

Many alcoholics become malnourished

(4)

•  Many alcoholics become malnourished, i.e., are deficient in vitamin and proteins
• Empty calories from ethanol oxidation
• Reduction in food intake
• Direct and indirect toxicities in GI tract with many functional consequences

DRUGS FOR ETHANOL DEPENDENCE

(12)

•  Disulfiram (Antabuse ®): inhibitor of ALDH, induces acetaldehyde syndrome
• Reduces # of drinking days but does not increase abstinence (consecutive non-drinking days) or craving
• Naltrexone (ReVia® oral; or Vivitrol ® im, 1-month duration) opioid antagonist
• Reduces # drinking days
• Enhances abstinence
• Reduces feelings of craving
• Acamprosate calcium (Campral ®): glutamate receptor antagonist
• Reduces # of drinking days and relapses
• May primarily work by reducing physiological signs of withdrawal
• Some efficacy reported with topiramate (Topamax®)
• Reduces # drinking days
• Increases # abstinent days

• disulfiram (Antabuse ®) (see metabolism section); inhibitor of aldehydedehydrogenase; induces acetaldehyde syndrome when ethanol is consumed
• in use for 50+ years, but relatively few, good clinical trials
• appears to mainly reduce number of drinking days; does not appear to enhance abstinence (i.e., number of consecutive non-drinking days) or reduce feelings of craving

Naltrexone (Revex)

(5)

• Naltrexone (ReVex ®)  opioid receptor antagonist, orally effective and long duration of action
• reduces number of drinking days and relapses
• enhances abstinence and reduces feelings of craving
• Animal studies suggest that ethanol enhances the release of endogenous opioid peptides (maybe through a pathway involving GABA), which in turn, increase the release  of dopamine in the reward pathway.  Thus, blocking the opioid receptor may reduce the rewarding actions of ethanol.
• Vivitrol ® is a new preparation, an injectable (IM) suspension with one month duration of action

Acamprosate Calcium (Campral)

(4)

• acamprosate  calcium(Campral ®)
• Neurochemical mechanism not established, may be an antagonist at subtype of glutamate receptor
• reduces number of drinking days and relapses
• may enhance abstinence by reducing physiological signs of withdrawal, esp. anxiety, insomnia

THE ACETALDEHYDE SYNDROME

(5)

•  Induced by disulfiram (Antabuse ®), inhibitor of acetaldehyde dehydrogenase, if ethanol is ingested; acetaldehyde accumulates.
• Tachycardia, hypotension, facial flushing
• Weakness, fainting
• Headache, nausea, vomiting
• Many Asians have increased ADH activity plus decreased ALDH activity and experience some degree of acetaldehyde syndrome with even light/modest ethanol intake

• Slide 44
•  ADH1a
• No known polymorphisms
• ADH1b
• ADH1B*2
• Common in Chinese, Japanese, Koreans,  Russians and Jews
• Faster (lower?) metabolism of alcohol,    (higher?) acetylaldehyde            abuse potential
• ADH1B3*
• 30% Africans,    (lower?)abuse potential
• ADH1c
• ADH1c*
• Slightly faster metabolism

•  ALDH2 is expressed in mitochondria
• ALDH2*s
• Individuals that are homozygous for loss of function mutation (5%-10% of Japanese, Chinese, and Korean) have severe reactions to alcohol
• VERY low risk for abuse
• Asian individuals heterozygous for this polymorphism ALDH2*2, 2*1, have milder responses to drinking. Flushed faces, tend to abuse less

•  KEY CONCEPTS  The defining features of FAS are:
• CNS dysfunctions, esp. mental retardation,
• growth retardation and
• facial dysmorphias. 
• Dose-response and time-response relationships have not been conclusively established

• The fetal alcohol syndrome is a set of characteristics exhibited by offspring of women who abuse alcohol during pregnancy.

FETAL ALCOHOL SYNDROME: CNS ABNORMALITIES

(3)

•  Mental retardation; impaired cognitive development and learning disabilities
• Poor coordination and feeding reflexes in infancy
• Attention deficit/hyperactivity disorder in childhood and adolescence

FETAL ALCOHOL SYNDROME: GROWTH ABNORMALITIES

(3)

FETAL ALCOHOL SYNDROME: FACIAL DYSMORPHIAS

(6)

FETAL ALCOHOL SYNDROME: FACIAL DYSMORPHIAS

Picture

•  Immature enzyme systems in fetus prolongs exposure to ethanol, acetaldehyde?
• Direct neurotoxicity
• Increased cell death
• Interference with cell division, differentiation, migration, neuronal connections
• ROS and mitochondrial dysfunction
• Excitotoxicity from withdrawal
• Retinoic acid and craniofacial abnormalities
• Maternal factors