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UNHEALTHY ALCOHOL USE
THE PROBLEM 8.2 million in US are alcohol
dependent Dependence =“ lack of control” 85,000 Deaths Disability-medical & psychiatric Secondhand effects-MVCs Cost $ 185 billion
UNHEALTHY ALCOHOL USE
EPIDEMIOLOGYPREVALENCE Outpatients 7-20% ED patients 30-40% Trauma patients 50%
ALCOHOL DEPENDENCEALCOHOLISM
• Clinically significant impairment or distress
with 3 or more:
Tolerance Continued use in spite of
Withdrawal psychological/physical
Time spent disability
Change in lifestyle
Desire to cut back
Copyright restrictions may apply.
Hasin, D. S. et al. Arch Gen Psychiatry 2007;64:830-842.
Hazard rates for age at onset of DSM-IV alcohol abuse and alcohol dependence
100 30 60 90 120 150
120 25 50 75 100 125
140 22 44 66 88 110
160 19 39 58 78 97
180 17 34 52 69 86
200 16 31 47 62 78
Drinks in one hour
Bod
y w
eig
ht
(pou
nds)
1 2 3 4 5
Blood alcohol concentration (BAC) mg/dl
Factors Affecting Ethanol Absorption
1. Concentration of ethanol 2. Blood flow at site of absorption
3. Irritant properties of ethanol 4. Rate of ingestion
5. Type of beverage
Absorption of ethanol from the duodenum and jejunum is much more rapid than from the stomach; hence the rate of gastric emptying is an important determinant of the rate of absorption of orally administered ethanol.
DISTRIBUTION: To body water. Women Men
General Scheme for Ethanol Oxidation
3. Most of this ethanol oxidation occurs in the liver
4. Ethanol cannot be stored in the liver
5. No major feedback mechanisms to pace the rate of ethanol metabolism to the physiological conditions of the liver cell
6. Kinetics are zero-order
OH + NAD+
ADHO + NADH + H+
O + NAD+ALDH
O
OH+ NADH + H+
O
OH
O
SCoACO2
Fatty acidsKetone bodiesCholesterol
1. < 10% ethanol excreted in breath, sweat and urine
2. ~ 90% ethanol removed by oxidation
METABOLISM OF ETHANOL
Alcohol dehydrogenase
Aldehyde dehydrogenase
Acetaldehyde
CH3CH2OH Ethanol
CH3C=O|H
AcetateCH3C=O|OH
Acetyl-CoA
CoAATP
NAD
NADH
NAD
NADH
Citric acidcycle
CO2 + H2O + Calories
Women have less ADH than men
Asians may have an inactive ALDH
ALCOHOL AND CARBOHYDRATE
METABOLISM
• Alcoholic hypoglycemia• Alcoholic ketoacidosis• Lactic acidosis
CONSEQUENCES OF INCREASED NADH/NAD RATIO
KETONEMIAKETONEMIA
LIVER
BLOOD
KIDNEY
LACTICACIDEMIA
LACTICACIDEMIA
HYPER-URICEMIA
HYPER-URICEMIA
Ethanol
Pyruvate
Lactate
Acetoacetate
-Hydroxybutyrate
Acetone
UrateGout ?
UrineSecretion
NAD
NADH
NAD
MECHANISM OF ALCOHOLIC HYPOGLYCEMIA
Liver Glycogen – Depleted by fasting
BLOODGLUCOSE Glucose
DHAP
Gluco- neogenesis
PEP
OAA
Pyruvate
-glycero- P
NAD NADHLactate
NADH NAD
NADH NAD
AlanineMalate
CONCENTRATIONDECREASED
BYETOH OXIDATION
MECHANISM FOR DECREASEDFATTY ACID OXIDATION
NADOAA
NADC18-FA-CoA + + FAD AcCoA + C16-FA-CoA+
NADH+
FADH2
TCA cycle+
respiratory chain
CO2 + H2O
LIVER TRIGLYCERIDE SYNTHESISINCREASED BY ETHANOL OXIDATION
ETHANOL OXIDATION
Acetyl-CoADihydroxyacetone
phosphate
Fatty Acids
NADP NADH
NADPH NAD
-glycerophosphate
Triglycerides
DISORDERS ASSOCIATED WITHINCREASING BLOOD ALCOHOL LEVELS:
DIRECT TOXIC EFFECTS
Adverse Effects on the Nervous System
• Intoxication • “Blackouts”• “Pathologic intoxication • Coma
Alcohol and Alcoholism
Nutritionaldeficiency
Pharmacologic Direct WithdrawalToxic effect Syndromes
LiverDisease
Unknown
ALCOHOL & THE BRAIN
GABA & GLUTAMATE
• STIMULATION
• SEDATION
• INTOXICATION
• WITHDRAWAL Sx
Low doses stimulate the gluta-
mate system with arousal &
increased energy
High doses inhibit glutamate ,
augment GABA suppressing
dopaminergic for sedation
DOPAMINE & OPIATE
• REINFORCEMENT,REW-ARD, & PLEASURE
• CRAVING
• SUSTAINED USE
• RELAPSE AFTER LONG ABSTINENCE
Endogenous opioids released
Inhibit GABA pathways and
enhance dopaminergic signals
Anton R. N Engl J Med 2008;359:715-721
Neurochemical Circuits Involved in Alcohol Dependence and Craving
ALCOHOL INTOXICATION
BEHAVIORAL SYNDROME• Exhilaration, excitement• Loquacity, assertiveness• Loss of behavioral inhibitions• Progresses to stupor and coma
CEREBELLAR SYNDROME• Dysarthria• Ataxia of gait and limbs• Progresses to marked generalized
loss of coordination
“ALCOHOLIC BLACKOUTS”
• Intoxicated but not drowsy or stuporous
• New memories not recorded during intoxication
• Duration of a few hours• Permanent retrograde amnesia for
period of intoxication• Mechanism not understood• No implications regarding prognosis
of alcoholism
ALCOHOLIC COMA: CLINICAL FEATURES
• Life threatening: not well appreciated• Often complicated by other drug
ingestion• Kills by respiratory depression or by
complicating states:- subdural hematoma - hypoglycemia- meningitis - pancreatitis- pneumonia - UGI hemorrhage- hypothermia - hepatitis
- portosystemic encephalopathy
ALCOHOL
• Polyneuropathy• Cerebellar atrophy• Pontine myelinolysis• WKS
• Wernicke - Korsakoff Syndrome (WKS)
• Wernicke’s
confusion
cranial nerve palseys
incoordination• Korsakoff’s
amnesia
confabulation
ALCOHOL: THE MAJOR CAUSEOF LIVER CIRRHOSISIN DEVELOPED NATIONS
Alcoholic cirrhosis(80%)
All other(20%)
Pathogenesis of Alcoholic Liver Injury
Theories Centrilobular hypoxia PMN infiltration & activation Inflammatory cell infiltration &
activation Antigenic adduct formation Injurious cytokines & endotoxin
ALCOHOL
• Heart - Cardiomyopathy• Peripheral vascular system- hypertension• Protective effect with moderate doses
Copyright restrictions may apply.
Sokol, R. J. et al. JAMA 2003;290:2996-2999.
Child With Facial Characteristics of Fetal Alcohol Syndrome
TOLERANCE TO CHRONIC ALCOHOL
METABOLICTOLERANCE
NEURONALTOLERANCE
INCREASEDCONSUMPTION
Decreasedblood level
Decreasedeffect
Increasedmetabolism
Increasedmetabolism
Kosten T and O'Connor P. N Engl J Med 2003;348:1786-1795
Medication Treatment for Alcohol Withdrawal
ALCOHOL WITHDRAWAL
• Benzodiazepines (lorazepam or others)
Decreased severity of withdrawal Sx
Reduced risk of seizures and DTs
LATE WITHDRAWAL: DELIRIUM TREMENS
• Profound confusion, disorientation, misperceptions
• Hallucinations, paranoid delusions• Motor hyperactivity: Tremor, restlessness,
agitation, hyperreflexia• Autonomic hyperactivity: Tachycardia,
profuse sweating, mydriasis• Leads to dehydration, hypotension, shock,
hyperthermia• Mortality: Inadequately treated10-15%
adequately treated 2-4%
ALCOHOLISM TREATMENT
• DISULFIRAM - ALDH INHIBITOR
• NALTREXONE - OPIOID ANTAGONIST
• ACAMPROSATE – MECHANISM ?
DrugsLI
VE
RB
LOO
D
AlcoholDehydrogenase
Acetaldehyde
Microsomes
Metabolites
Alcohol Drugs
LIV
ER
BLO
OD
AlcoholDehydrogenase
Acetaldehyde
Microsomes
Metabolites
Alcohol
Drugs
LIV
ER
BLO
OD
AlcoholDehydrogenase
Acetaldehyde
Microsomes
Metabolites
Alcohol Drugs
LIV
ER
BLO
OD
AlcoholDehydrogenase
Acetaldehyde
Microsomes
Metabolites
Alcohol
A B
C D
Lee, W. M. N Engl J Med 2003;349:474-485
The Role of Ethanol in the Formation of N-acetyl-p-benzoquinone-imine (NAPQI), the Toxic Metabolite of Acetaminophen (APAP), and the Dynamics of Enzyme Induction